Review ArticleClinical StudiesR

Genetic Determinants of Cardiovascular Disease: The Renin-Angiotensin-Aldosterone System, Paraoxonases, Endothelin-1, Nitric Oxide Synthase and Adrenergic Receptors

ANNA GLUBA, MACIEJ BANACH, DIMITRI P. MIKHAILIDIS and JACEK RYSZ
In Vivo September 2009, 23 (5) 797-812;

Abstract

Apart from conventional risk factors such as cigarette smoking, obesity, hypertension, diabetes mellitus, hypercholesterolemia, physical inactivity and metabolic syndrome, a family history of coronary artery disease (CAD) seems to be important, especially in young people. Among the genes that may potentially influence the onset and the progression of CAD, there are those controlling the following: renin-angiotensin-aldosterone system (RAAS), adrenergic receptors, paraoxonases, endothelin and nitric oxide synthase. They may modulate the risk of disease onset, as well as its progression and patient prognosis. The unravelling of genetic determinants of CAD may be the first step towards a better understanding of the pathological process involved, the early identification of those at risk and individualizing treatment.

Abbreviations: ACE, Angiotensin-converting enzyme; ACE-I, angiotensin-converting enzyme inhibitor; AGT, angiotensinogen; AngII, angiotensin II; T1, AT2, angiotensin II type 1 and 2 receptor, respectively; CAD, coronary artery disease; COX-2, cyclooxygenase 2; CYP11B2, aldosterone synthase gene; eNOS, NOS-3, nitric oxide synthase; ENaC, epithelial sodium channels; ETA, ETB, endothelin receptors, types A and B, respectively; ET-1, endothelin 1; ICAM-1, intercellular adhesion molecule 1; IL, interleukin; LDL, low-density lipoprotein; MI, myocardial infarction; MMP, metalloproteinase; MPC-1, monocyte chemoattractant protein 1; NAD(P)H, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; ox-LDL, oxidative low-density lipoprotein; PAI-1, tissue plasminogen activator inhibitor; PON, paraoxonase; RAAS, renin-angiotensin-aldosterone system; ROMK, renal outer medullary potassium channel; TF, tissue factor; TGF-β, transforming growth factor-β; TNF-α, tissue necrosis factor α; t-PA, tissue plasminogen activator; VEGFR-2, vascular endothelial growth factor 2.

Cardiovascular disease is the main cause of mortality and morbidity in the world (1). As for example, every day 200-250 Poles die of myocardial infarction (MI) and it causes nearly 20% of deaths in people under 65 years of age (1). According to epidemiological data prepared on the basis of the Polish NATPOL PLUS study with the use of the PRECARD algorithm, the number of Poles aged 30-70 with MI in Poland will reach 740,000 during the next 10 years (2). The proportion of premature MI is constantly growing (3), and accounts for 10% of all infarcts (4). Interestingly, the phenomenon of MI without atherosclerosis, which is quite uncommon in older patients, occurs in 20% of premature MI cases (5). In up to 51% of young patients (6), MI manifests as a single-vessel disease and it may be particularly dangerous (high risk of sudden cardiac death) due to the fact that the collateral circulation, which probably helps to maintain flow within the myocardium (7), is less developed (8).

Cardiovascular disease is influenced by both environmental and genetic factors. According to Kraus et al. (9), genetic factors contribute to 20-60% of coronary artery disease (CAD) cases, having a more pronounced impact on disease development in young patients than do environmental factors (10). Apart from conventional risk factors such as cigarette smoking, obesity, hypertension, diabetes mellitus, hypercholesterolemia, physical inactivity and metabolic syndrome, a family history of CAD is important, especially in young people (5, 11-13). A positive family history of cardiovascular disease is defined as the occurrence of CAD or an MI event in a first-degree relative up to the age of 55 years in men or 65 years in women (11). According to the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2) study, 42% of premature acute MI (AMI) patients had a positive family history of CAD (11). Marenberg et al. (14) demonstrated that the risk of death from CAD at an early age is higher in monozygotic twins than in dizygotic twins, especially when one twin died before the age of 55 years in men or 65 years in women. This risk decreased with the increasing age of fatal CAD occurrence in the affected twin (14). Further research suggests that a positive sibling history is a better predictor of coronary atherosclerosis than is a parental history of premature CAD (15). However, the genetic mechanisms associated with family history of CAD remain undiscovered.

The implementation of prevention and diagnostic programs of cardiovascular diseases, which may lead to the decrease of the morbidity rate, is of high importance. Unravelling the genetic determinants of this disease may be the first step towards understanding the pathological process and may further lead to the early identification of people at risk and to personalized disease prevention and therapy. The awareness of having predisposition towards CAD may be a motivation for some people to introduce changes into their lifestyles, such as changing dietary habits or quitting smoking (16). However, the unequivocal identification of genes responsible for the genesis and progression of such disease is difficult due to the fact that disease expression depends on the cumulative effects of both genetic and environmental factors, and that the same disease in different patients may be triggered by different factors (17). According to numerous studies, single nucleotide polymorphisms (SNPs) do not usually determine the expression of CAD, but they merely predispose its progression in association with environmental factors.

Numerous genes and variants with plausible effects on the cardiovascular system have been studied; however, the results have been inconsistent. This may be explained partially by ethnic diversity, differences in experimental designs and gene by environment interactions. Among the genes which may potentially influence the onset and the progression of CAD, there are these controlling the following: renin-angiotensin-aldosterone system (RAAS), adrenergic receptors, paraoxonases, endothelin, nitric oxide synthase (NOS) and natriuretic peptides.

The Renin-Angiotensin-Aldosterone System (RAAS)

The RAAS takes part in the pathogenesis of numerous cardiovascular diseases including MI (18), hypertrophy (19), cardiomyopathy (20), atrial fibrillation (21) and congestive heart failure (22). Activation of this system may not only lead to the occurrence of cardiovascular events but may also promote the development of heart failure after MI (16). RAAS plays an important role in the regulation of the fibrinolytic system (23), since, as was shown in both in vitro and in vivo studies, angiotensin II increases the level of tissue plasminogen activator inhibitor (PAI-1), which is the main physiological inhibitor of fibrinolysis (23-25).

Angiotensin (Ang)-converting enzyme (ACE). The enzyme responsible for cleaving AngI into vasoconstrictor peptide AngII is angiotensin-converting enzyme (ACE). Unfavourable influence of ACE on the circulatory system is caused by the fact that it generates AngII and hydrolyses bradykinin, which stimulates the production and secretion of prostacyclin, nitric oxide (NO), and tissue plasminogen activator (t-PA), thereby diminishing its beneficial vasorelaxant, antiplatelet and fibrinolytic effect on endothelium (26, 27). This enzyme, a potent vasoconstrictor, participates in the regulation of vascular tone, increases platelet activation and aggregation of platelets (23).

On the basis of studies conducted on mice with insertionally inactivated ACE gene in which blood pressure was lower than in mice with functional gene, Krege et al. (28) suggested that this enzyme is necessary for maintaining proper blood tension. The diminishing frequency of ischaemic events (29, 30) and the improvement in endothelium function (31), after the application of ACE inhibitors (ACE-I) confirm the thesis that ACE participates in the pathogenesis of cardiovascular disease. The I/D polymorphism within the ACE gene, characterized by the presence or absence of a 287-base pair sequence comprising all repeats, is responsible for about 50% of individual variability in the level of circulating serum ACE. The level of enzyme is about 2-fold higher in DD homozygotes than in II homozygotes, whereas the heterozygotes show intermediary concentrations (23). This polymorphism within intron 16 leads to the deletion of the gene expression ‘silencer’ region (32) and, as a consequence, the increase of ACE in serum and tissues (33, 34). According to Tokunaga et al. (35), the DD genotype is associated not only with a higher concentration of ACE in blood, but also with its higher activity in heart muscle cell. Detection polymorphism of ACE has been thoroughly researched and is considered a potential risk factor for cardiovascular disease. I/D polymorphism has been linked with the increased risk of MI in several studies (36-40), CAD (39), idiopathic dilated cardiomyopathy, recurrent ischaemic events (41) and left ventricle hypertrophy (42, 43).

The DD genotype has been linked with carotid intimamedia thickening (44) and an elevated risk of restenosis after stenting (45). It has been suggested that the DD haplotype may increase plaque instability (46), probably through accelerating the rate of low-density lipoprotein (LDL) particle influx into arterial walls, which results in an increased lipid content in plaque (47), as well as through promoting endothelial cell dysfunction and vascular smooth muscle cell proliferation (48, 49). On the basis of research conducted on patients who had experienced an MI event within the previous 4 to 7 months, Ohmichi et al. (50) concluded that the D allele influenced ejection fraction and the end-systolic volume index. McNamara et al. (51) suggested that the presence of the D allele is not associated with the occurrence of MI, but may modulate the rate of disease progression. The determination of ACE polymorphism may be important while choosing an efficient beta-blocker therapy, since, as demonstrated by McNamara et al. (51), only DD carriers benefited from it: their survival after transplantations was increased.

Angiotensinogen. Another part of the RAAS within which polymorphisms may contribute to the pathogenesis of CAD is angiotensinogen (AGT). It is conversed by renin into AngI and further cleaved to AngII. Being the main AngII precursor, AGT poses an important determinant of its level both in serum and tissues (52). Many polymorphisms were identified within the AGT gene. The most frequently studied SNPs are: M235T and T174M (in the coding region) and G(−6)A and A(−20)C (in the promoter region). Some of them are associated with an increased risk of CAD (53), extent of coronary atherosclerosis (54) and hypertension (55) in many but not all studies (56).

Angiotensinogen concentration is a factor which limits AngII generation (57), thus its increased amount may boost the AngII level, promote atherosclerosis (58) or modulate the severity of CAD (59).

According to Tsai et al. (60), M235T is a non-functional polymorphism which serves only as a genetic marker. This SNP is in complete linkage disequilibrium with G(−6)A polymorphism (61) located in the transcription factor binding region (62). Allele −6A (235Thr) is associated with increased gene transcription (63) and, as a consequence, with elevated levels of serum angiotensinogen (64). Azizi et al. (65) demonstrated that polymorphism Met235Thr leads to diminished peptide clearance. In addition, T174M was found to be in a tight linkage disequilibrium with M235T (66). Sethi et al. (67) showed that the 235TT genotype is linked with significantly higher blood pressure, especially among women, but it does not influence the risk of CAD. However, Tsai et al. (60) revealed that in women with hypertension, the risk of CAD is increased in the presence of the M235T polymorphism. The AGT haplotypes were more markedly associated with CAD in women, probably either due to the fact that the angiotensinogen gene contains an estrogen response element which stimulates this peptide's synthesis (68) or that estrogens potentiate the effect of AngII (60, 69). Met235Thr polymorphism may affect blood pressure and influence the course of cardiovascular disease. A meta-analysis conducted by Kunz et al. (55) showed that Met235Thr significantly increased the risk of hypertension among patients with positive family history. In a population of young Poles (under 55 years), this SNP was associated with CAD and MI (70).

Angiotensin II. AngII, the most potent element of the RAAS, takes part in the pathogenesis of atherosclerosis (71), hypertension, heart failure, cardiac hypertrophy and renal damage (72). It mediates in the onset of all the aforementioned diseases by the activation of transcription factors, redox signalling systems, and stimulation of production and secretion (73) of endogenous growth factors (e.g. platelet-derived growth factor, transforming growth factor-α (TGF-α), insulin-like growth factor-I), cytokines (e.g. interleukin-6 (IL-6), IL-1), and chemokines (e.g. monocyte chemoattractant protein-1 (MPC-1) and IL-8) (74). AngII exerts its detrimental effects including vasoconstriction, cell growth regulation, inflammation and fibrosis (72), pressor responses and aldosterone secretion (75) mainly through receptor AT1 (76) associated with protein Gq and phospholipase C (16). AngII may participate in the formation of atherosclerotic plaque mainly via the induction of adhesion molecule expression in human endothelial cells (77) and monocyte activation leading to their enhanced adhesion to endothelial cells (78) as well as in plaque development through the stimulation of the growth (79), migration (48) and matrix generation (80) in smooth muscle cells. AngII is also a chemotactic agent for T lymphocytes (80, 81). It also stimulates the activity of membrane-bound NAD(P)H oxidase which produces reactive oxygen species (ROS) (82) in vascular smooth muscle and endothelial cells (82) and induces oxidative stress in macrophages (83). ROS lead to the formation of oxidised LDL (ox-LDL) particles, which seem to be pivotal in the formation and development of the atherosclerotic plaque in coronary vessels (84).

Apart from increasing oxidative stress, AngII enhances intracellular ox-LDL uptake (85) and the differentiation of monocytes into macrophages (73). Through the stimulation of IL-6, intercellular adhesion molecule 1 (ICAM-1) and MPC-1 protein, AngII induces the inflammatory process (73). By inducing local inflammation and also by activation of metalloproteinases (MMP-1, MMP-2 and MMP-9) (74), AngII contributes to plaque instability and its rupture (86). Schieffer et al. (86) demonstrated the presence of AngII and its receptor next to the presumed plaque rupture site in coronary artery fragments harvested from patients who died of MI. Moreover, AngII induces the process of fibroblast proliferation and increases collagen synthesis via the enhancement of TGF-α synthesis (16). AngII stimulates the generation of tissue plasminogen activator inhibitor (PAI-1) and tissue factor (TF) via increasing the synthesis of TNF-α (87). It triggers myocytes and vascular smooth muscle cell compensatory hypertrophy, which may lead to the limitation of blood flow and further to the development of myocardial ischaemia (88). Through the receptor AT1, AngII indirectly contributes to increased calcium inflow into myocyte interior and, as a consequence, to enhanced cardiac contractility (16). It also influences the strength of cardiac contractions by the stimulation of noradrenaline secretion from nerve terminals (89).

AT1 activation was also demonstrated to be responsible for AngII-dependent apoptosis both in vitro (90) and in vivo (91) studies. AngII takes part in the pathogenesis of arterial hypertension, which is an important risk factor for CAD, directly through smooth muscle cell vasoconstriction and indirectly by stimulation of the adrenal cortex to secrete aldosterone, which in turn leads to the increase of intravascular volume (93). Moreover, AngII influences the secretion of the potent vasoconstrictor endothelin (94) and vasopressin and reduces NO bioavailability via generation of ROS, which has considerable effect on endothelium-dependent vasodilatation (94). Nowadays, the two products of N-terminal degradation of AngII, namely Ang III and IV, are raising considerable interest. AngIV has been determined to mediate important physiological functions of the central nervous system, such as blood flow regulation, and to be associated with cognitive processes and sensory and motor functions (76). Some studies suggest that AngII has to be converted into AngIII to be able to bind with AT1 and AT2 receptors, and is further cleaved into AngIV in order to activate AT4 receptors (76).

As far as we know, no polymorphisms within the AngII gene have yet been described, probably due to the fact that most scientists concentrate on the receptor through which AngII exerts its detrimental effects. The most often studied polymorphism within the AngII type I receptor (AT1) gene is an adenine/cytosine (A/C) base substitution at position −1166 in the 3’ untranslated region of the gene (75, 95-97). The polymorphism has been linked with essential hypertension (96), enhanced coronary artery vasoconstriction (97) and cardiac hypertrophy (98). Allele C was observed in patients who suffered from drug-resistant hypertension (96) and those with a strong family history (99). Allele −1166C has been associated in some studies with increased responses to AngII (95), which boosted the unfavourable influence of AngII on the cardiovascular system (100). However, Tiret et al. (101) suggested that the AT1 C allele is in linkage disequilibrium with another functional mutation which influences AngII responsiveness via altering receptor down-regulation in response to AngII. According to Diez et al. (102), the 1166A/C polymorphism is associated with the synthesis of type I collagen and myocardial stiffness in patients suffering from hypertensive cardiovascular disease (75). In other studies, it has been demonstrated that −1166C allele influenced the hypertrophy phenotype (98), was connected with lower ejection fraction (103, 104), increased left ventricular mass index (103, 105), higher end-systolic volume (105) and higher risk of MI among concurrent carriers of ACE D allele (101).

The role of AT2 receptor has not yet been well studied. According to Wolf (106) activation of AT2 by AngII may, in some circumstances, stimulate in vivo growth and could have important pathophysiological consequences. Another study suggests that through AT2, AngII may inhibit proliferation of certain cells and induce apoptosis (107). However, the reports concerning the role of AT2 are often contradictory (108-110).

Aldosterone. Aldosterone is a steroid hormone which plays an important role in the pathogenesis of arterial hypertension (111), arteriosclerosis, left ventricle hypertrophy (112), arrhythmia (113), cardiovascular disease (114) and chronic renal disease (114). It is secreted by the zona glomerulosa of the adrenal gland cortex and its main function is the regulation of body water-electrolyte balance and blood pressure. At first, it was believed that aldosterone acted only in coiled duct (cortical collecting tubule) where after binding to cytosolic receptors it regulated potassium (renal outer medullary potassium channel, ROMK) and epithelial sodium (ENaC) channels thus increasing the reabsorption of sodium ions (Na+) and the secretion of potassium ions (K+) into the urine (115, 116). It was then found that aldosterone might also be synthesized by smooth muscle cells, endothelium and cardiomyocytes, and its actions were much more systemic (116). The overall effect of physiological levels of aldosterone is to decrease the rate of sodium ion excretion, increase the secretion of potassium and water retention, and to enhance blood pressure.

Aldosterone acts either directly through mineralocorticoid receptors (MR) or via enhancing AngII and endothelin expression, COX-2 activation and the increase of oxidative stress (115, 116). Recently, it has been shown that aldosterone action may be also mediated by membrane receptors and these effects occur shortly after aldosterone exposure as this pathway does not involve transcription and protein production (113).

Excessive secretion of aldosterone which binds to mineralocorticoid receptors localized in heart, blood vessels and brain may lead to myocardium and vessel hypertrophy (through type I and III collagen transcription stimulation) (117), endothelial dysfunction (through the decrease of NO release) and to severe coronary artery damage (via the generation of inflammatory infiltrations) (113). Studies of animal models revealed that a high concentration of aldosterone in myocardium may stimulate the formation of inflammatory infiltrations comprising macrophages, T lymphocytes, monocytes and the proteins of the complement system, which suggest that this hormone may participate in the process of immunocompetent cell activation (118). Moreover, aldosterone may cause reduced baroreceptor sensitivity and interfere with norepinephrine uptake by myocardium and, as a consequence, may induce adverse heart rate variability and catecholamine-induced arrhythmias (113). According to Marumo et al. (119), aldosterone inhibits bone marrow cell differentiation by reducing the expression of vascular endothelial growth factor 2 (VEGFR-2) and in this way, it negatively influences endothelium reconstruction. The enhancement of NADPH oxidase activity by this mineralocorticoid hormone leads to higher oxidative stress which in turn stimulates proinflammatory processes and intensifies the synthesis of some growth factors (120).

The contribution of aldosterone to the pathogenesis of cardiovascular disease was confirmed in studies on transgenic mice with the increased expression of human mineralocorticoid receptor, which demonstrated their high susceptibility to arrhythmia and frequent sudden deaths (121). Moreover, promotion of aldosterone binding to mineralocorticoid receptors induced rat heart hypertrophy, fibrosis and heart failure, with no symptoms of hypertension (122). In addition, according to Cohn and Colucci (113), the local production of aldosterone, dependent on the degree of myocardial impairment and failure, increases after MI. Cardiac remodelling in which the hormone participates leads to the change of left ventricle architecture, systolic function impairment and is an indicator of unfavourable prognosis after MI (113). According to Biondi-Zoccai et al. (123), aldosterone directly induces myocardial apoptosis. It also promotes myocardial ischaemia and necrosis and contributes to PAI-1 regulation (113). The reduced mortality and morbidity in clinical studies of post-acute MI patients in which aldosterone blockade was used confirm the participation of aldosterone in the pathogenesis of cardiovascular disease (113).

No polymorphism influencing the risk of CAD or MI has been characterized within the aldosterone gene. However, it was demonstrated that several SNPs occur within the gene of CYP11B2 (a key enzyme of aldosterone synthesis). Polymorphisms in aldosterone synthase may contribute to severe low-renin hypertension and left ventricle remodeling (124). The 334T/C polymorphism in the CYP11B2 gene is located near the transcription factor SF-1-binding site and may influence the expression (125, 126) of steroid biosynthetic enzymes in the adrenal cortex (127). However, due to the fact that another SF-1 binding site located downstream from the promoter is much more important for transcriptional control, it was suggested that a site neighbouring the −344 polymorphism is essential for developmental regulation of CYP11B2 in the adrenal or in extra-adrenal sites (124). According to Kupari et al. (124), the −344C allele binds in in vitro studies about 4 times stronger than the −344T. Carriers of the C allele have higher aldosterone concentration and increased risk of cardiovascular disease. The −344T/C polymorphism has been associated in many studies with the increase of left ventricle size and its impaired filling in young Caucasians (124) as well as with hypertension (126, 128). Healthy individuals carrying the −344C allele demonstrated up to 28% larger end-diastolic volumes and left ventricle mass 21% greater in comparison to 344TT homozygotes (124).

Paraoxonases (PON)

The defence against the detrimental effect of LDL oxidation is based on antioxidative and anti-inflammatory properties of high-density lipoprotein (HDL) and HDL-associated enzymes (129) such as: paraoxonases, apolipoprotein A-I, and Apo J (130, 131). To date, three isoforms of paraoxonases (PON) have been discovered (132), two of which are bound with HDL particles (PON1 and PON3), whereas the third is present in smooth muscle cells, endothelium and macrophages (133), where it exerts its antioxidant effect at a cellular level (134). PON1 inhibits lipoprotein oxidation and catalyses the hydrolysis of already existing lipid peroxides and other active metabolites such as organophosphate compounds (135). According to Aviram et al. (136), PON1 can also decompose reactive hydrogen peroxide which is generated in arterial walls during atherosclerotic plaque development. PON2 has been demonstrated to participate in the defence against LDL oxidation as well (134). Despite years of strenuous scientific research, the activity of PONs which mediate their anti-atherogenic effects has not been ascertained yet (137). It has been suggested that it is the lactonase activity preventing vessel damage via the degradation of toxic lactone which constitutes their main biological feature, since neither PON1 nor PON2 exhibits activity toward paraoxon (138-140). This hypothesis was confirmed by studies of PON1 mutants, in which decreased lactonase activity was associated with diminished anti-atherogenic properties (137). This activity has been shown to play a role in the inhibition of LDL oxidation as well as in the hydrolysis of oxidized lipids in macrophages (137). However, other studies demonstrated that low PON activity toward paraoxon is connected with cardiovascular risk (141, 142).

Polymorphisms lowering the expression of PONs or diminishing their activity may lead to atherosclerosis development. Numerous studies concerning the role of PONs in protection against atherosclerosis revealed the association between the PON1 Arg192 allele and increased risk of CAD (143-145), although the results were not always consistent (146, 147). The substitution of Gln by Arg in position 192 seems to be very important in the ability of PON1 to protect LDL from oxidation. In comparison to 192Arg, the Gln allele was associated with higher arylesterase activity (148) toward paraoxon, higher efficiency in oxidation inhibition (149) and better protection (150, 151). PON1 participation in the inhibition of ox-LDL generation may suggest that its activity modulates susceptibility to atherosclerosis and its development (152). Studies conducted on PON1 knock-out mice demonstrated that they were more prone to the development of diet-induced atherosclerotic plaque, and the HDL isolated from them was not able to prevent lipoproteins to oxidation in vitro (153). The polymorphism Ser311Cys in PON2, situated in the potential active centre of oxidative lipid hydrolysis, may influence the catalytic activity of this enzyme (145). According to Martinelli et al. (154), PON2 polymorphism was associated with increased risk of CAD especially among smokers. Moreover, Sanghera et al. (145) and Chen et al. (155) found a connection between Ser311Cys polymorphism and CAD risk. The latter authors demonstrated significant association between the occurrence of 192Arg and 311Cys alleles and the severity of cardiovascular disease. In their study, Arg and Cys alleles were over represented in patients with 3-vessel disease in comparison to those with lower a number of diseased vessels (155). According to Sanghera et al. (145) the lack of connection between Gln192Arg and Ser311Cys occurrence and the concentration of lipids and apolipoproteins may suggest that the increased risk of heart failure linked with the presence of these polymorphisms is independent of the conventional plasma lipid profile. Due to the fact that the activity and level of serum PON protein differs significantly between individuals and populations of varied ethnic backgrounds (156), some studies have suggested that not only the genotype of PONs, but also their activity and concentration influence the risk of cardiovascular disease (142, 157).

Endothelin-1 (ET-1)

Endothelial dysfunction, defined as the disturbance of the balance between vasodilatory and vasoconstrictor properties, plays an important role in the formation and progression of atherosclerotic plaque as well as in pathogenesis of heart failure (158). Both vascular relaxation impairment and increased constriction may lead to the development of hypertension, the damage of endothelium and plaque formation and rupture (159). Endothelial vasoconstrictor features depend mainly on endothelin-1 (ET-1) which is produced mainly in vascular endothelial cells in the form of pre-proendothelin-1 (160). This 212 amino acid peptide is further cleaved by furin to generate a biologically inactive ‘big ET-1’. The formation of mature ET-1 requires transformation by endothelin-converting enzyme into the 21-amino acid vasoconstrictor peptide (161). Apart from being a potent vasoconstrictor, ET-1 has inotropic, chemotactic and mitogenic properties (160). The effect of ET-1 is mediated through two types of receptors: ETA located on vascular muscle cells (162), which takes part in vasoconstrictor activity of ET-1; and ETB located on endothelial cells (163), the activation of which leads to stimulation of NO and prostaglandin production, and vasodilation (159). ET-1 through the ETA receptors induces vascular smooth muscle cell proliferation (164). It favours the formation of inflammatory infiltrations through stimulation of monocyte production of cytokines (TNF, IL-1, -6 and -8, granulocyte-macrophage colony-stimulating factor) (165), the adhesion of neutrophilic granulocytes and platelet aggregation (166), which may lead to the development of ischaemic disease. ET-1 induces the release of other vasoconstrictor factors such as: vasopressin, AngII, adrenaline, noradrenaline, thromboxane A2 and aldosterone (167). The biological effects of ET-1 also include the influence on salt and water homeostasis, stimulation of both the sympathetic systems and cardiac contraction (inotropic and chronotropic effects). It was demonstrated that the concentration of ET-1 was increased in patients suffering from hypertension (168), acute coronary syndrome (169) and MI (170). ET-1 participates not only in the genesis but also in the progression of atherosclerosis: its increased levels were detected in the serum of patients in the early stage of plaque formation and in individuals with advanced, disseminated atherosclerosis. Nessler et al. (171) also revealed a tight correlation between this peptide concentration and the amount of atherosclerotic lesions in coronary arteries.

The effectiveness of endothelin antagonists in the treatment of vasoconstriction-induced cardiac, vascular and renal diseases including essential hypertension (172) confirms the role of ET-1 in the pathogenesis of these diseases. The functional significance of the polymorphism 198Lys/Asn localized near the C-terminal fragment of pre-proendothelin is not known, however, it was suggested that it may be involved in ET-1 function, as it may affect the processing of pre-proET-1 to mature ET-1 (173). The obtained protein may be non-functional and unable to exert its detrimental effect in pathological states. According to studies, this polymorphism was associated with the alteration of vascular reactivity (174), with increased resting pressure among middle-aged individuals (173, 175) and increased risk of heart failure (176).

Nitric Oxide Synthase (NOS-3, eNOS)

NO, synthesized from L-arginine by endothelial NO synthase (eNOS coded by NOS-3), promotes vasodilation, limits the oxidation of atherogenic LDL (177), plays a key role in reducing vascular smooth muscle cell (VSMC) proliferation, platelet adhesion (178, 179), endothelial permeability and extracellular matrix collagen synthesis. It takes part in the maintenance of endothelial function and vascular homeostasis among others through the regulation of vascular tone (180) and blood pressure (181). NO reduces vascular smooth muscle cell mitogenesis (anti-proliferative effect), restricts chemotaxis (182) and limits leukocyte adhesion to endothelial cells (179, 183). It prevents LDL oxidation (180) and inhibits ROS release (182), thus lowering the adverse impact of oxidative LDL particles on the endothelium (180). Moreover, NO can influence blood coagulation (181) and exert anti-atherogenic effects through blunting the activity of nuclear-kappa B transcription factors leading to the decreased expression of cytokines and adhesion molecules (184). The endothelial isoform of NOS is constitutively expressed, but in for example shear stress conditions, endothelial cells respond with a compensatory increase in NOS-3 expression in order to maintain physiological functions in a pathological state (185). However, the reactive nitric species generated in inflammatory state, hypercholesterolemia, diabetes mellitus and hypertension may lead to a further damage of cellular structures (186). According to numerous studies, the impairment of NO synthesis leads to the progression of endothelial dysfunction (187), vasoconstriction and the formation of thrombi (188) and as has been observed in animal models, it promotes the formation of atherosclerotic plaque (189, 190).

This is why it was suggested that polymorphisms within the NOS-3 gene which reduce either the expression of synthase or NO availability may contribute to the progression of cardiovascular disease (191). As yet, several polymorphisms in the NOS-3 gene such as 786T/C, 922A/G, 894G/T, G10T, 27 bp tandem repeat in intron 4 and −1444T/A have been identified, and in some studies, but not in all (192-195), they have been linked with an increased risk of CAD (196, 197), hypertension (198,199), coronary spasm (200) and in-stent restenosis (201). The 894G/T polymorphism bringing about the 298Glu/Asp substitution, according to Tesauro et al. (202) leads to the formation of NOS protein more susceptible to cleavage, which in turn results in the reduction of the functional protein level. However, in vitro studies indicated that between various allele products, there are no differences (203) in stability or activity (204). Joshi et al. (205) suggested that eNOS Glu/Asp and Asp/As variants may have different caveolae localization which might influence the biological activity of NO signal molecule and signal transduction (206). According to Agema et al. (207), among TT homozygotes the risk of cardiovascular disease and MI is elevated. It has been also concluded that the 894G/T polymorphism may be very useful in the identification of people at high risk of atherosclerosis (208). Another polymorphism within the NOS-3 gene, 786T/C, has been demonstrated to be associated with reduced promoter activity, reduced platelet release of NO (209) and lower response to shear stress (191). Protein A1 (replication repressor) (210) binds to the C allele and leads to diminished transcription rate and lower serum nitrite/nitrate levels in normal conditions and in hypoxia (209). This polymorphism contributed in an Italian population both to endothelial dysfunction and increased risk of CAD (211, 211), and in Japanese patients to coronary spasm (209). Joint presence of 894G/T and 786T/C was associated not only with the incidence, but also with the severity of angiographically proven congestive heart failure (213). Jeerooburkhan et al. (192) observed the relation between the occurrence of 786T/C and 922A/G polymorphisms. This tendency was confirmed by Nakayama et al. (209) who demonstrated a strong association between three polymorphisms within the NOS-3 gene (786 T/C, 922 A/G and 1468 T/A) and coronary spasm. According to Yoon et al. (214) the frequency of occurrence of another polymorphism (G10T) within the intron 23 of the NOS-3 gene is much higher in patients suffering from heart failure than in healthy individuals. Although the mechanism of this polymorphism is not known, it was suggested that due to the fact that the motif identical to the original splicing site is created in the T allele, it may lead to aberrant splicing of the primary NOS-3 gene transcript and thus influence the enzyme activity (215).

Adrenergic Receptors

Regulatory systems, the activation of which play a role in the pathogenesis of heart failure and cardiac remodelling are the RAAS (mentioned above) and the sympathetic system (216). Prolonged stimulation of the adrenergic system in pathological states leads to further circulatory impairment and cardiovascular disease progression, since catecholamines released during activation exert a detrimental effect on the heart via adrenergic receptors (217). The sympathetic and RAAS systems are activated to maintain normal cardiac output, however, in the state of irreversible cardiac damage, their stimulation leads to increase in cardiac load, left ventricle geometry change and dysfunction (218). The adrenergic receptors are a class of G protein-coupled receptors that are activated by catecholamines (adrenaline, noradrenaline). The activation of β receptors through the Gs protein stimulates adenyl cyclase and leads to contractility increase, whereas α1 receptors activate Gq protein and the phospholipase C signalling pathway (217). The stimulation of α1 and β adrenergic receptors by noradrenaline may result in increased collagen synthesis and further lead to cardiac fibrosis, cardiac hypertrophy and heart remodelling (217). Prolonged stimulation of β1 receptors leads to the increase of intracellular calcium (Ca2+) concentration, successive cardiomyocyte calcium overload and cell necrosis (217). Noradrenaline may modulate the process of apoptosis (219) through β1 adrenergic receptors. In contrast to β1 receptors, β2 may exhibit cardioprotective properties. Studies on animal models demonstrated that β2 receptor activation inhibited cardiomyocyte apoptosis, probably due to the stimulation of inhibitory protein Gi (220). The β1 adrenergic receptors which are in the majority in the heart and participate in the physiological effect of noradrenaline release from sympathetic nerve endings (cardiac inotropy and chronotropy), seem to be one of the main factors taking part in the pathogenesis of cardiovascular disease (220). Stimulation of β1 receptors results in an increase in heart rate, higher cardiac contractility and renin synthesis enhancement, which in turn leads to perturbation of blood flow, increased vascular tone and finally to endothelial damage and atherosclerotic plaque rupture (221).

According to numerous studies (217, 222-224), prolonged adrenergic system activation underlies the pathogenesis of congestive heart failure. The application of β blockers in the treatment after MI reduces mortality as well as the risk of future events (225). The polymorphisms within the genes of adrenergic receptors, which either ameliorate the function of β1 receptors or diminish the expression of β2, have adverse effects on the circulatory system. The presence of hyperfunctional polymorphism in the 1165 position (Arg389Gly) within the critical point for G protein-coupling in β1 receptor localized on cardiomyocytes, according to Biolol et al. (226) may result in enhanced receptor function and myocyte contractile response to stimulation. However, this observation was true only in initial stages, since in older mice, the 389Arg allele was associated with reduced signalling, worse receptor binding and lower ventricular contraction (227). The Arg389 carriers were more susceptible to β-blocker treatment and their ventricular function was much more improved compared with 389Gly carriers (227).

Another polymorphism in the β1 receptor in position 49 (Ser/Gly) has been linked with higher activity of adenyl cyclase (217), higher agonist and antagonist affinity (220), better response to inhibition by metoprolol (226) and greater down-regulation and desensitization by catecholamines (226). This polymorphism is considered ‘protective’ as it was demonstrated to be associated with greater survival rate and lower number of cardiovascular complications in heart failure patients (217). Joint occurrence of Arg389 and a polymorphism within the α2c receptor that regulates norepinephrine release is thought to be a CAD risk factor (228). Among all polymorphisms within the β2 adrenergic receptor gene, Thr164Ile has been analysed in most studies. This substitution is associated with diminished adenyl cyclase activity (impaired binding to Gs protein) (229, 230), reduced affinity towards agonists (215) and depressed myocardial contractile function (231). According to Ligget et al. (232), the survival rate among patients with ischaemic or dilated cardiomyopathy carrying the 164Ile allele was much lower than in 164Thr carriers (42% vs. 76%, p<0.001). Variant 164Ile contributed to faster progression of heart failure (232). Other polymorphisms within the β2 gene such as Arg16Glu and Gln27Glu have also been linked with the course of cardiovascular disease (217). Allele 16Gly increases receptor down-regulation, whereas the Glu27 allele seems to prevent the decrease in receptor numbers during their enhanced stimulation (217).

Polymorphisms within α adrenergic receptors which regulate the norepinephrine release may lead to higher susceptibility to heart failure (233, 226). The deletion of four amino acids in α2c adrenergic receptor (Del322-325) interferes with its function and contributes to lower auto-inhibitory activity and higher norepinephrine levels (234, 226). As mentioned before, the occurrence of this polymorphism and 389Arg allele (β1 receptor) was associated with a 10-fold increased the risk of heart failure in African-American patients (228).

Conclusion

Polymorphisms within the genes of the RAAS system, ET-1, NOS and adrenergic system may contribute to the development and progression of cardiovascular disease. Although the potential functionality of some of these polymorphisms is known, the consequences of the occurrence of given alleles are not unequivocal. Current knowledge and learning supports the notion that in order to gain a more complete understanding of the mechanisms underlying cardiovascular disease initiation and progression, we need to incorporate into study designs and analyses the concept of environment genotype and genotype interactions. The unravelling of genetic determinants of vascular disease will help identify people at risk, introduce strategies for disease prevention and early-stage treatment and allow individualized treatment.

  • Received March 23, 2009.
  • Revision received June 2, 2009.
  • Accepted June 24, 2009.

References

  1. 1.↵
    1. Kowalski J,
    2. Barylski M,
    3. Banach M,
    4. Grycewicz J,
    5. Irzmański R,
    6. Pawlicki L
    : Neutrophil superoxide anion generation during atorvastatin and fluvastatin therapy used in coronary heart disease primary prevention. J Cardiovasc Pharmacol 48: 143-147, 2006.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Boncler M,
    2. Gresner P,
    3. Nocun M,
    4. Rywaniak J,
    5. Dolnik M,
    6. Rysz J,
    7. Wilk R,
    8. Czyz M,
    9. Markuszewski L,
    10. Banach M,
    11. Watala C
    : Elevated cholesterol reduces acetylsalicylic acid-mediated platelet acetylation. Biochim Biophys Acta 1770: 1651-1659, 2007.
    OpenUrlPubMed
  3. 3.↵
    1. McAllister HA Jr..,
    2. Hall RJ,
    3. Cooley DA
    : Tumors of the heart and pericardium. Curr Probl Cardiol 24: 57-116, 1999.
    OpenUrlPubMed
  4. 4.↵
    1. Masajtis A,
    2. Barylski M,
    3. Banach M,
    4. Rysz J,
    5. Drożdż J
    : Zawal mięśnia sercowego - narastający problem u mlodych osób. Przew Lek 2: 74-79, 2006.
    OpenUrl
  5. 5.↵
    1. Choudhury L,
    2. Marsh J
    : Myocardial infarction in young patients. Am J Med 107: 254-261, 1999.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Klein LW,
    2. Agarwal JB,
    3. Herlich MB,
    4. Leary TM,
    5. Helfant RH
    : Prognosis of symptomatic coronary artery disease in young adults aged 40 years or less. Am J Cardiol 60: 1269-1272, 1987.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Petronio AS,
    2. Baglini R,
    3. Limbruno U,
    4. Mengozzi G,
    5. Amoroso G,
    6. Cantarelli A,
    7. Vaghetti M,
    8. Distante A,
    9. Balbarini A,
    10. Mariani M
    : Coronary collateral circulation behaviour and myocardial viability in chronic total occlusion treated with coronary angioplasty. Eur Heart J 19: 1681-1687, 1998.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Banach M,
    2. Rysz J,
    3. Goch A,
    4. Mikhailidis DP,
    5. Rosano GM
    : The role of trimetazidine after acute myocardial infarction. Curr Vasc Pharmacol 6: 282-291, 2008.
    OpenUrlPubMed
  9. 9.↵
    1. Kraus WE
    : Genetic approaches for the investigation of genes associated with coronary heart disease. Am Heart J 140: S27-S35, 2000.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Chaer RA,
    2. Billeh R,
    3. Massad MG
    : Genetics and gene manipulation therapy of premature coronary artery disease. Cardiology 101: 122-130, 2004.
    OpenUrlCrossRefPubMed
  11. 11.↵
    1. O'Donnell CJ
    : Family history, subclinical atherosclerosis, and coronary heart disease risk barriers and opportunities for the use of family history information in risk prediction and prevention. Circulation 110: 2074-2076, 2004.
    OpenUrlFREE Full Text
  12. 12.
    1. Williams RR,
    2. Hunt SC,
    3. Heiss G,
    4. Province MA,
    5. Bensen JT,
    6. Higgins M,
    7. Chamberlain RM,
    8. Ware J,
    9. Hopkins PN
    : Usefulness of cardiovascular family history data for population-based preventive medicine and medical research (the Health Family Tree Study and the NHLBI Family Heart Study). Am J Cardiol 87: 129-135, 2001.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Kowalski J,
    2. Banach M,
    3. Barylski M,
    4. Irzmanski R,
    5. Pawlicki L
    : Carvedilol modifies antioxidant status of patients with stable angina. Cell Mol Biol Lett 13: 230-239, 2008.
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. Marenberg ME,
    2. Risch N,
    3. Berkman LF,
    4. Floderus B,
    5. de Faire U
    : Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med 330: 1041-1046, 1994.
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. Nasir K,
    2. Michos ED,
    3. Rumberger JA,
    4. Braunstein JB,
    5. Wendy S,
    6. Post WS,
    7. Matthew J,
    8. Budoff MJ,
    9. Blumenthal RS
    : Coronary artery calcification and family history of premature coronary heart disease: sibling history is more strongly associated than parental history. Circulation 110: 2150-2156, 2004
    OpenUrlAbstract/FREE Full Text
  16. 16.↵
    1. Piestrzeniewicz K,
    2. Luczak K,
    3. Maciejewski M,
    4. Goch JH
    : Impact of obesity and adipokines on cardiac structure and function in men with first myocardial infarction. Arch Med Sci 4: 152-160, 2008.
    OpenUrl
  17. 17.↵
    1. Wojtczak A,
    2. Skrętkowicz J
    : Genetics in ischaemic heart disease. Pol Merk Lek 23: 133-135, 2007.
    OpenUrl
  18. 18.↵
    1. Hanatani A,
    2. Yoshiyama M,
    3. Kim S,
    4. Omura T,
    5. Toda I,
    6. Akioka K,
    7. Teragaki M,
    8. Takeuchi K,
    9. Iwao H,
    10. Takeda T
    : Inhibition by angiotensin II type I receptor antagonist of cardiac phenotypic modulation after myocardial infarction. J Mol Cell Cardiol 27: 1905-1914, 1995.
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. Brilla CG,
    2. Pick R,
    3. Tan LB,
    4. Janicki JS,
    5. Weber KT
    : Remodeling of the rat right and left ventricles in experimental hypertension. Circ Res 67: 1355-1364, 1990.
    OpenUrlAbstract/FREE Full Text
  20. 20.↵
    1. Urata H,
    2. Boehm KD,
    3. Philip A,
    4. Kinoshita A,
    5. Gabrovsek J,
    6. Bumpus FM,
    7. Husain A
    : Cellular localization and regional distribution of an angiotensin II forming chymase in the heart. J Clin Invest 91: 1269-1281, 1993.
    OpenUrlCrossRefPubMed
  21. 21.↵
    1. Tsai CT,
    2. Lai LP,
    3. Lin JL,
    4. Chiang FT,
    5. Hwang JJ,
    6. Ritchie MD,
    7. Moore JH,
    8. Hsu KL,
    9. Tseng CD,
    10. Liau CS,
    11. Tseng YZ
    : Renin-angiotensin system gene polymorphisms and atrial fibrillation. Circulation 109: 1640-1646, 2004.
    OpenUrlAbstract/FREE Full Text
  22. 22.↵
    1. Weber KT,
    2. Brilla CG,
    3. Janicki JS
    : Myocardial fibrosis: functional significance and regulatory factors. Cardiovasc Res 27: 341-348, 1993.
    OpenUrlFREE Full Text
  23. 23.↵
    1. von Depka M,
    2. Czwalinna A,
    3. Wermes C,
    4. Eisert R,
    5. Scharrer I,
    6. Ganser A,
    7. Ehrenforth S
    : The deletion polymorphism in the angiotensin-converting enzyme gene is a moderate risk factor for venous thromboembolism. Thromb Haemost 89: 847-852, 2003.
    OpenUrlPubMed
  24. 24.
    1. Ridker PM,
    2. Gaboury CL,
    3. Conlin PR,
    4. Seely EW,
    5. Williams GH,
    6. Vaughan DE
    : Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II: evidence of a potential interaction between the renin-angiotensin system and fibrinolytic function. Circulation 87: 1969-1973, 1993.
    OpenUrlAbstract/FREE Full Text
  25. 25.↵
    1. Vaughan DE,
    2. Lazos SA,
    3. Tonk K
    : Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells: a potential link between the renin-angiotensin system and thrombosis. J Clin Invest 95: 995-1001, 1995.
    OpenUrlCrossRefPubMed
  26. 26.↵
    1. Soubrier F,
    2. Wei L,
    3. Hubert C,
    4. Clauser E,
    5. Alhenc-Gelas F,
    6. Corvol P
    : Molecular biology of the angiotensin I-converting enzyme: part II. Structure-function. Gene polymorphism and clinical implications. J Hypert 11: 599-604, 1993.
    OpenUrlCrossRefPubMed
  27. 27.↵
    1. Kowalczyk E,
    2. Kopff M,
    3. Kowalski J,
    4. Kopff A,
    5. Mikhailidis DP,
    6. Barylski M,
    7. Banach M
    : Effect of cardiovascular drugs on adenosine deaminase activity. Angiology 59: 740-744, 2009.
    OpenUrl
  28. 28.↵
    1. Krege JH,
    2. John SWM,
    3. Langenbach LL,
    4. Hodgin JB,
    5. Hagaman JR,
    6. Bachman ES,
    7. Jennette JC,
    8. O'Brien DA,
    9. Smithies O
    . Male-female differences in fertility and blood pressure in ACE-deficient mice. Nature 375: 146-148, 1995.
    OpenUrlCrossRefPubMed
  29. 29.↵
    1. Yusuf S,
    2. Pepine CJ,
    3. Garces C,
    4. Pouleur H,
    5. Salem D,
    6. Kostis J,
    7. Benedict C,
    8. Rousseau M,
    9. Bourassa M,
    10. Pitt B
    : Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fraction. Lancet 340: 1173-1178, 1992.
    OpenUrlCrossRefPubMed
  30. 30.↵
    1. Pfeffer MA,
    2. Braunwald E,
    3. Moyé LA,
    4. Basta L,
    5. Brown EJ Jr.,
    6. Cuddy TE,
    7. Davis BR,
    8. Geltman EM,
    9. Goldman S,
    10. Flaker GC
    : Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction - results of the survival and ventricular enlargement trial. N Engl J Med 327: 669-677, 1992.
    OpenUrlCrossRefPubMed
  31. 31.↵
    1. O'Driscoll G,
    2. Green D,
    3. Rankin J
    : Improvement in endothelial function by angiotensin converting enzyme inhibition in insulin-dependent diabetes mellitus. J Clin Invest 100: 678-684, 1997.
    OpenUrlCrossRefPubMed
  32. 32.↵
    1. Rigat B,
    2. Hubert C,
    3. Corvol P,
    4. Soubrier F
    : PCR detection of the insertion/deletion polymorphism of the human angiotensin I converting enzyme gene (DCPI). Nucleic Acids Res 20: 1433, 1992.
    OpenUrlFREE Full Text
  33. 33.↵
    1. Tiret L,
    2. Rigat B,
    3. Visvikis S,
    4. Breda C,
    5. Corvol P,
    6. Cambien F,
    7. Soubrier F
    : Evidence from combined segregation and linkage analysis that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE. Am J Hum Genet 51: 197-205, 1992.
    OpenUrlPubMed
  34. 34.↵
    1. Rigat B,
    2. Hubert C,
    3. Alhenc-Gelas F,
    4. Cambien F,
    5. Corvol P,
    6. Soubrier F
    : An insertion/deletion polymorphism in the angiotensin I converting gene accounting for half the variance of serum enzyme levels. J Clin Invest 86: 1343-1346, 1990.
    OpenUrlCrossRefPubMed
  35. 35.↵
    1. Tokunaga S,
    2. Tsuji H,
    3. Nishiue T,
    4. Yamada K,
    5. Miysaka Y,
    6. Saitou D,
    7. Iwasaka T
    : Lower mortality in patients with the DD genotype of the angiotensin-converting enzyme gene after acute myocardial infarction. Acta Cardiol 56: 351-355, 2001.
    OpenUrlPubMed
  36. 36.↵
    1. Cambien F,
    2. Poirier O,
    3. Lecerf L,
    4. Evans A,
    5. Cambou JP,
    6. Arveiler D,
    7. Luc G,
    8. Bard JM,
    9. Bara L,
    10. Ricard S,
    11. Tiret L,
    12. Amouyel P,
    13. Alhenc-Gelas P,
    14. Soubrier F
    : Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 359: 641-644, 1992.
    OpenUrlCrossRefPubMed
  37. 37.
    1. Samani NJ,
    2. Thompson JR,
    3. O'Toole L,
    4. Channer K,
    5. Woods KL
    : A meta-analysis of the association of the deletion allele of the angiotensin-converting enzyme gene with myocardial infarction. Circulation 94: 708-712, 1996.
    OpenUrlAbstract/FREE Full Text
  38. 38.
    1. Ludwig EH,
    2. Comeli PS,
    3. Anderson JL,
    4. Marshall HW,
    5. Lalouel JM,
    6. Ward RH
    : Angiotensin-converting enzyme gene polymorphism is associated with myocardial infarction but not with development of coronary stenosis. Circulation 91: 2120-2124, 1995.
    OpenUrlAbstract/FREE Full Text
  39. 39.↵
    1. Nakai K,
    2. Itoh C,
    3. Miura Y,
    4. Hotta K,
    5. Musha T,
    6. Itoh T,
    7. Miyakawa T,
    8. Iwasaki R,
    9. Hiramori K
    : Deletion polymorphism of the angiotensin I-converting enzyme gene is associated with serum ACE concentration and increased risk for CAD in the Japanese. Circulation 90: 2199-2202, 1994.
    OpenUrlAbstract/FREE Full Text
  40. 40.↵
    1. Agerholm-Larsen B,
    2. Nordestgaard BG,
    3. Tybjaerg-Hansen A
    : ACE gene polymorphism in cardiovascular disease. Meta-analysis of small and large studies in whites. Arterioscler Thromb Vasc Biol 20: 484-492, 2000.
    OpenUrlAbstract/FREE Full Text
  41. 41.↵
    1. van Geel PP,
    2. Pinto YM,
    3. Zwinderman AH,
    4. Henning RH,
    5. Van Boven AJ,
    6. Jukema J.W,
    7. Bruschke A,
    8. Kastelein J,
    9. van Gilst WH,
    10. Baxter G
    : Increased risk for ischaemic events is related to combined RAS polymorphism. Heart 85: 458-462, 2001.
    OpenUrlAbstract/FREE Full Text
  42. 42.↵
    1. Raynolds MV,
    2. Bristow MR,
    3. Bush EW,
    4. Abraham WT,
    5. Lowes BD,
    6. Zisman LS,
    7. Taft CS,
    8. Perryman MB
    : Angiotensin-converting enzyme DD genotype in patients with ischemic or idiopathic dilated cardiomyopathy. Lancet 342: 1073-1075, 1993.
    OpenUrlCrossRefPubMed
  43. 43.↵
    1. Ohmichi N,
    2. Iwai N,
    3. Maeda K,
    4. Shimoike H,
    5. Nakamuray Y,
    6. Izumi M,
    7. Sugimoto Y,
    8. Kinoshita M
    : Genetic basis of left ventricular remodeling after myocardial infarction. Int J Cardiol 53: 265-272, 1996.
    OpenUrlCrossRefPubMed
  44. 44.↵
    1. Castellano M,
    2. Muiesan ML,
    3. Rizzoni D,
    4. Pasini G,
    5. Cinelli A,
    6. Salvetti M,
    7. Porteri E,
    8. Bettoni G,
    9. Kreutz R,
    10. Lindpaintner K,
    11. Rosei EA
    : Angiotensin-converting enzyme I/D polymorphism and arterial wall thickness in a general population: the Vobarno study. Circulation 91: 2721-2724, 1995.
    OpenUrlAbstract/FREE Full Text
  45. 45.↵
    1. Amant C,
    2. Bauters C,
    3. Bodart J-C,
    4. Lablanche J-M,
    5. Grollier G,
    6. Danchin N,
    7. Hamon M,
    8. Richard F,
    9. Helbecque N,
    10. McFadden EP,
    11. Amouyel P,
    12. Bertrand ME
    : D allele of the angiotensin I-converting enzyme is a major risk factor for restenosis after coronary stenting. Circulation 96: 56-60, 1997.
    OpenUrlAbstract/FREE Full Text
  46. 46.↵
    1. Samani NJ,
    2. Martin DS,
    3. Brack M,
    4. Cullen J,
    5. Chauhan A,
    6. Lodwick D,
    7. Harley A,
    8. Swales JD,
    9. de Bono DP,
    10. Gershlicka AH
    : Insertion/deletion polymorphism in the angiotensin-converting enzyme gene and risk of restenosis after coronary angioplasty. Lancet 345: 1013-1016, 1995.
    OpenUrlCrossRefPubMed
  47. 47.↵
    1. Kane JP,
    2. Malloy MJ,
    3. Ports TA,
    4. Phillips NR,
    5. Diehl JC,
    6. Havel RJ
    : Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. JAMA 264: 3007-3012, 1990.
    OpenUrlCrossRefPubMed
  48. 48.↵
    1. Daeman MJP,
    2. Lombardi DM,
    3. Bosman FT,
    4. Schwartz SM
    : Angiotensin II induces smooth muscle proliferation in the normal and injured rat arterial wall. Circ Res 68: 450-456, 1991.
    OpenUrlAbstract/FREE Full Text
  49. 49.↵
    1. O'Malley JP,
    2. Maslen CL,
    3. Illingworth DR
    : Angiotensin-converting enzyme DD genotype and cardiovascular disease in heterozygous familial hypercholesterolemia. Circulation 97: 1780-1783, 1998.
    OpenUrlAbstract/FREE Full Text
  50. 50.↵
    1. Ohmichi N,
    2. Iwai N,
    3. Nakamura Y,
    4. Kinoshita M
    : The genotype of the angiotensin-converting enzyme gene and global left ventricular dysfunction after myocardial infarction. Am J Cardiol 76: 326-329, 1995.
    OpenUrlCrossRefPubMed
  51. 51.↵
    1. McNamara DM,
    2. Holubkov R,
    3. Janosko K,
    4. Palmer A,
    5. Wang JJ,
    6. MacGowan G.A,
    7. Murali S,
    8. Rosenblum WD,
    9. London B,
    10. Feldman AM
    : Pharmacogenetic interactions between β-blocker therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure. Circulation 103: 1644-1648, 2001.
    OpenUrlAbstract/FREE Full Text
  52. 52.↵
    1. Reid IA,
    2. Morris BJ,
    3. Ganong WJ
    : The renin-angiotensin system. Annu Rev Physiol 40: 377-410, 1978.
    OpenUrlCrossRefPubMed
  53. 53.↵
    1. Nguyen DC,
    2. Hamaguchi K,
    3. Saikawa T,
    4. Hara M,
    5. Sakata T
    : A polymorphism of angiotensinogen gene codon 174 and coronary artery disease in Japanese subjects. (Abstract). Am J Med Sci 316: 289-328, 1998.
    OpenUrl
  54. 54.↵
    1. Gardemann A,
    2. Stricker J,
    3. Humme J,
    4. Nguyen QD,
    5. Katz N,
    6. Philipp M,
    7. Tillmanns H,
    8. Hehrlein FW,
    9. Haberbosch W
    : Angiotensinogen T174M and M235T gene polymorphisms are associated with the extent of coronary atherosclerosis. Atherosclerosis 145: 433-436, 1999.
    OpenUrl
  55. 55.↵
    1. Kunz R,
    2. Kreutz R,
    3. Beige J,
    4. Distler A,
    5. Sharma AM
    : Association between the angiotensinogen 235T-variant and essential hypertension in whites: a systematic review and methodological appraisal. Hypertension 30: 1331-1337, 1997.
    OpenUrlAbstract/FREE Full Text
  56. 56.↵
    1. Ko YL,
    2. Ko YS,
    3. Wang SM,
    4. Chu PH,
    5. Teng MS,
    6. Cheng NJ,
    7. Chen WJ,
    8. Hsu TS,
    9. Kuo CT,
    10. Chiang CW,
    11. Lee YS
    : Angiotensinogen and angiotensin-I converting enzyme gene polymorphisms and the risk of coronary artery disease in Chinese. Hum Genet 100: 210-214, 1997.
    OpenUrlCrossRefPubMed
  57. 57.↵
    1. Gould AB
    : Kinetics of the human renin and human substrate reaction. Cardiovasc Res 5: 86-89, 1971.
    OpenUrlAbstract/FREE Full Text
  58. 58.↵
    1. Ishigami T,
    2. Umemura S,
    3. Iwamoto T,
    4. Tamura K,
    5. Hibi K,
    6. Yamaguchi S,
    7. Nyuui N,
    8. Kimura K,
    9. Miyazaki N,
    10. Ishii M
    : Molecular variant of angiotensinogen gene is associated with coronary atherosclerosis. Circulation 91: 951-954, 1995.
    OpenUrlAbstract/FREE Full Text
  59. 59.↵
    1. Lanz JR,
    2. Pereira AC,
    3. Lemos PA,
    4. Martinez E,
    5. Krieger JE
    : Angiotensinogen M235T polymorphism is associated with coronary artery disease severity. Clin Chim Acta 362: 176-181, 2005.
    OpenUrlCrossRefPubMed
  60. 60.↵
    1. Tsai CT,
    2. Hwang JJ,
    3. Lai LP,
    4. Wang YC,
    5. Lin JL,
    6. Chiang FT
    : Interaction of gender, hypertension, and the angiotensinogen gene haplotypes on the risk of coronary artery disease in a large angiographic cohort. Atherosclerosis 203: 249-256, 2009.
    OpenUrlPubMed
  61. 61.↵
    1. Sato N,
    2. Katsuya T,
    3. Nakagawa T,
    4. Ishikawa K,
    5. Fu Y,
    6. Asai T,
    7. Fukuda M,
    8. Suzuki F,
    9. Nakamura Y,
    10. Higaki J,
    11. Ogihara T
    : Nine polymorphisms of angiotensinogen gene in the susceptibility to essential hypertension. Life Sci 68: 259-272, 2000.
    OpenUrlCrossRefPubMed
  62. 62.↵
    1. Davis D,
    2. Liyou N,
    3. Lockwood D,
    4. Johnson A
    : Angiotensinogen genotype, plasma protein and mRNA concentration in isolated systolic hypertension. Clin Genet 61: 363-368, 2002.
    OpenUrlCrossRefPubMed
  63. 63.↵
    1. Inuoe I,
    2. Nakajima T,
    3. Williams CS,
    4. Quackenbush J,
    5. Puryear R,
    6. Powers M,
    7. Cheng T,
    8. Ludwig EH,
    9. Sharma AM,
    10. Hata A,
    11. Jeunemaitre X,
    12. Lalouel JM
    : A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro. J Clin Invest 99: 1786-1797, 1997.
    OpenUrlCrossRefPubMed
  64. 64.↵
    1. Staessen JA,
    2. Kuznetsova T,
    3. Wang JG,
    4. Emelianov D,
    5. Vlietinck R,
    6. Fagard R
    : M235T angiotensinogen gene polymorphism and cardiovascular renal risk. J Hypertens 17: 9-17, 1999.
    OpenUrlCrossRefPubMed
  65. 65.↵
    1. Azizi M,
    2. Hallouin MC,
    3. Jeunemaitre X,
    4. Guyene TT,
    5. Ménard J
    : Influence of the M235T polymorphism of human angiotensinogen (AGT) on plasma AGT and renin concentrations after ethinylestradiol administration. J Clin Endocr Metab 85: 4331-4337, 2000.
    OpenUrlCrossRefPubMed
  66. 66.↵
    1. Jeunemaitre X,
    2. Soubrier F,
    3. Kotelevtsev Y,
    4. Lifton R,
    5. Williams CS,
    6. Charru A,
    7. Hunt SC,
    8. Hopkins PN,
    9. Williams RR,
    10. Lalouel JM,
    11. Corvol P
    : Molecular basis of human hypertension: role of angiotensinogen. Cell 71: 169-180, 1992.
    OpenUrlCrossRefPubMed
  67. 67.↵
    1. Sethi AA,
    2. Nordestgaard BG,
    3. Gronholdt ML,
    4. Steffensen R,
    5. Jensen G,
    6. Tybjærg-Hansen A
    : Angiotensinogen single nucleotide polymorphisms, elevated blood pressure, and risk of cardiovascular disease. Hypertension 41: 1202-1211, 2003.
    OpenUrlAbstract/FREE Full Text
  68. 68.↵
    1. Clauser E,
    2. Gaillard I,
    3. Wei L,
    4. Corvol P
    : Regulation of angiotensinogen gene. Am J Hypertens 2: 403-410, 1989.
    OpenUrlPubMed
  69. 69.↵
    1. Kisley LR,
    2. Sakai RR,
    3. Flanagan-Cato LM,
    4. Fluharty SJ
    : Estrogen increases angiotensin II-induced c-Fos expression in the vasopressinergic neurons of the paraventricular nucleus in the female rat. Neuroendocrinology 72: 306-317, 2000.
    OpenUrlCrossRefPubMed
  70. 70.↵
    1. Buraczyńska M,
    2. Dzida G,
    3. Puźniak A,
    4. Sobstyl J,
    5. Hanzlik J
    : Association between angiotensinogen and atrial natriuretic peptide gene polymorphisms and increased risk of coronary heart disease. Kardiol Pol 53: 103-106, 2000 (in Polish).
    OpenUrl
  71. 71.↵
    1. Nickenig G,
    2. Harrison DG
    : The AT1-type angiotensin receptor in oxidative stress and atherogenesis, part I: oxidative stress and atherogenesis. Circulation 105: 393-396. 2002.
    OpenUrlFREE Full Text
  72. 72.↵
    1. Ruiz-Ortega M,
    2. Esteban V,
    3. Egido J
    : The regulation of the inflammatory response through nuclear factor-κB pathway by angiotensin IV extends the role of the renin angiotensin system in cardiovascular diseases. (Abstract). Trends Cardiovasc Med 17: 19-25, 2007.
    OpenUrlCrossRefPubMed
  73. 73.↵
    1. Ruiz-Ortega M,
    2. Lorenzo O,
    3. Esteban V,
    4. Suzuki Y,
    5. Mezzano S,
    6. Plaza JJ,
    7. Egido J
    : Role of the Renin-Angiotensin System in Vascular Diseases Expanding the Field. Hypertension 38: 1382-1387, 2001.
    OpenUrlAbstract/FREE Full Text
  74. 74.↵
    1. Weiss D,
    2. Sorescu D,
    3. Taylor WR
    : Angiotensin II and atherosclerosis. Am J Cardiol 87 suppl: 25C-32C, 2001.
    OpenUrl
  75. 75.↵
    1. Baudin B
    : Polymorphism in angiotensin II receptor genes and hypertension. Exp Physiol 90: 277-182, 2005.
    OpenUrlCrossRefPubMed
  76. 76.↵
    1. de Gasparo M,
    2. Catt KJ,
    3. Inagami T,
    4. Wright JW,
    5. Unger T
    : International Union of Pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev 52: 415-472, 2000.
    OpenUrlAbstract/FREE Full Text
  77. 77.↵
    1. Gräfe M,
    2. Graf K,
    3. Auch-Schwelk W,
    4. Hertel H,
    5. Hoffmann R,
    6. Bartsch P,
    7. Fleck E
    : Modulation of adhesion molecule expression in human coronary endothelial cells. Eur Heart J 14: 58-58, 1993 (abstract).
    OpenUrl
  78. 78.↵
    1. Hahn AWA,
    2. Jonas U,
    3. Buhler FR,
    4. Resink TJ
    : Activation of human peripheral monocytes by angiotensin II. FEBS Lett 347: 178-180, 1994.
    OpenUrlCrossRefPubMed
  79. 79.↵
    1. Itoh H,
    2. Pratt RE,
    3. Gibbons G,
    4. Dzau VJ
    : Multiple autocrine growth factors mutate vascular smooth muscle cell growth response to angiotensin II. J Clin Invest 91: 2268-2274, 1993.
    OpenUrlCrossRefPubMed
  80. 80.↵
    1. Diet F,
    2. Pratt RE,
    3. Berry GJ,
    4. Momose N,
    5. Gibbons GH,
    6. Dzau VJ
    : Increased accumulation of tissue ACE in human atherosclerotic coronary artery disease. Circulation 94: 2756-2767, 1996.
    OpenUrlAbstract/FREE Full Text
  81. 81.↵
    1. Weinstock JV,
    2. Blum AM,
    3. Kassab JT
    : Angiotensin II is chemotactic for a T-cell subset which can express migration inhibition factor activity in murine schistosomiasis mansoni. Cell Immunol 107: 180-187, 1987.
    OpenUrlCrossRefPubMed
  82. 82.↵
    1. Griendling KK,
    2. Minieri CA,
    3. Ollerenshaw JD,
    4. Alexander RW
    : Angiotensin II stimulates NADH and NADPH oxidase activation in cultured vascular smooth muscle cells. Circ Res 74: 1141-1148, 1994.
    OpenUrlAbstract/FREE Full Text
  83. 83.↵
    1. Yanagitani Y,
    2. Rakugi H,
    3. Okamura A,
    4. Moriguchi K,
    5. Takiuchi S,
    6. Ohishi M
    : Angiotensin II type 1 receptor-mediated peroxide production in human macrophages. Hypertension 33(1 Pt-2): 335-339, 1999.
    OpenUrlAbstract/FREE Full Text
  84. 84.↵
    1. Landmesser U,
    2. Drexler H
    : Oxidative stress, the renin-angiotensin system, and atherosclerosis. Eur Heart J Suppl 5 suppl A: A3-A7, 2003.
    OpenUrlAbstract
  85. 85.↵
    1. Keidar S,
    2. Attias J
    : Angiotensin II injection into mice increases the uptake of oxidized LDL by their macrophages via a proteoglycan-mediated pathway. Biochem Biophys Res Commun 239: 63-67, 1997.
    OpenUrlCrossRefPubMed
  86. 86.↵
    1. Schieffer E,
    2. Schieffer B,
    3. Hilfiker-Kleiner D,
    4. Hilfiker A,
    5. Kovanen PT,
    6. Kaartinen M,
    7. Nussberger J,
    8. Harringer W,
    9. Drexler H
    : Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability. Circulation 101: 1372-1378, 2000.
    OpenUrlAbstract/FREE Full Text
  87. 87.↵
    1. Barylski M,
    2. Kowalczyk E,
    3. Banach M,
    4. Ciecwierz J,
    5. Pawlicki L,
    6. Kowalski J
    : Plasma total antioxidant activity in comparison with plasma NO and VEGF levels in patients with metabolic syndrome. Angiology 60: 87-92, 2009.
    OpenUrlPubMed
  88. 88.↵
    1. Griffin SA,
    2. Brown WC,
    3. MacPherson F,
    4. McGrath JC,
    5. Wilson VG,
    6. Korsgaard N,
    7. Mulvany MJ,
    8. Lever AF
    : Angiotensin II causes vascular hypertrophy in part by a non-pressor mechanism. Hypertension 17: 626-635, 1991.
    OpenUrlAbstract/FREE Full Text
  89. 89.↵
    1. Cox S,
    2. Ben A,
    3. Story DF,
    4. Ziogas J
    : Evidence for the involvement of different receptor subtypes in the pre- and postjunctional actions of angiotensin II at rat sympathetic neuroeffector sites. Br J Pharmacol 114: 1057-1063, 1995.
    OpenUrlPubMed
  90. 90.↵
    1. Dayuan L,
    2. Baichun Y,
    3. Philips MI,
    4. Mehta JL
    : Proapoptotic effects of ANG II in human coronary artery endothelial cells: role of AT1 receptor and PKC activation. Am J Physiol Heart Circ Physiol 45: H786-H792, 1999.
    OpenUrl
  91. 91.↵
    1. Diep QN,
    2. Li JS,
    3. Schiffrin EL
    : In vivo study of AT1 and AT2 angiotensin receptors in apoptosis in rat blood vessels. Hypertension 34: 617-624, 1999.
    OpenUrlAbstract/FREE Full Text
  92. 93.↵
    1. Sayer JW,
    2. Timmis AD
    : Angiotensin-converting enzyme inhibitors and coronary artery disease. Cardiovasc Drugs Therapy 10 suppl 2: 631-637, 1996.
    OpenUrl
  93. 94.↵
    1. Kurland L,
    2. Melhus H,
    3. Sarabi M,
    4. Millgard J,
    5. Ljunghall S,
    6. Lind L
    : Polymorphisms in the renin-angiotensin system and endothelium-dependent vasodilation in normotensive subjects. Clin Physiol 21: 343-349, 2001.
    OpenUrlCrossRefPubMed
  94. 95.↵
    1. van Geel PP,
    2. Pinto YM,
    3. Voors AA,
    4. Buikema H,
    5. Oosterga M,
    6. Crijns HJGM,
    7. van Gilst WH
    : Angiotensin II type 1 receptor A1166C gene polymorphism is associated with an increased response to angiotensin II in human arteries. Hypertension 35: 717-721, 2000.
    OpenUrlAbstract/FREE Full Text
  95. 96.↵
    1. Bonnardeaux A,
    2. Davies E,
    3. Jeunemaitre X,
    4. Ferry I,
    5. Charru A,
    6. Clauser E,
    7. Tiret L,
    8. Cambien F,
    9. Corvol P,
    10. Soubrier F
    : Angiotensin II type 1 receptor gene polymorphism in human essential hypertension. Hypertension 24: 63-69, 1994.
    OpenUrlAbstract/FREE Full Text
  96. 97.↵
    1. Amant C,
    2. Hamon M,
    3. Bauters C,
    4. Richard F,
    5. Helbecque N,
    6. McFadden EP,
    7. Escudero X,
    8. Lablanche JM,
    9. Amouyel P,
    10. Bertrand ME
    : The angiotensin II type 1 receptor gene polymorphism is associated with coronary artery vasoconstriction. J Am Coll Cardiol 29: 486-490, 1997.
    OpenUrlCrossRefPubMed
  97. 98.↵
    1. Osterop AP,
    2. Kofflard MJ,
    3. Sandkuijl LA,
    4. ten Cate FJ,
    5. Krams R,
    6. Schalekamp MA,
    7. Danser AH
    : AT1 receptor A/C 1166 polymorphism contributes to cardiac hypertrophy in subjects with hypertrophic cardiomyopathy. Hypertension 32: 825-830, 1998.
    OpenUrlAbstract/FREE Full Text
  98. 99.↵
    1. Wang WY,
    2. Zee RY,
    3. Morris BJ
    : Association of angiotensin II type 1 receptor gene polymorphism with essential hypertension. Clin Genet 51: 31-34, 1997.
    OpenUrlPubMed
  99. 100.↵
    1. Spiering W,
    2. Spiering W,
    3. Kroon AA,
    4. Fuss-Lejeune MMJJ,
    5. Daemen MJAP,
    6. de Leeuw PW
    : Angiotensin II sensitivity is associated with the angiotensin II type 1 receptor A(1166)C polymorphism in essential hypertensives on a high sodium diet. Hypertension 36: 411-416, 2000.
    OpenUrlAbstract/FREE Full Text
  100. 101.↵
    1. Tiret L,
    2. Bonnardeaux A,
    3. Poirier O,
    4. Ricard S,
    5. Marques-Vidal P,
    6. Evans A,
    7. Arveiler D,
    8. Luc G,
    9. Kee F,
    10. Ducimetière P
    : Synergistic effects of angiotensin-converting enzyme and angiotensin-II type 1 receptor gene polymorphisms on risk of myocardial infarction. Lancet 344: 910-913, 1994.
    OpenUrlCrossRefPubMed
  101. 102.↵
    1. Diez J,
    2. Laviades C,
    3. Orbe J,
    4. Zalba G,
    5. Lopez B,
    6. Gonzalez A,
    7. Mayor G,
    8. Páramo JA,
    9. Beloqui O
    : The A1166C polymorphism of the AT1 receptor gene is associated with collagen type I synthesis and myocardial stiffness in hypertensives. Hypertension 21: 2085-2092, 2003.
    OpenUrl
  102. 103.↵
    1. Andersson B,
    2. Blange I,
    3. Sylven C
    : Angiotensin-II type 1 receptor gene polymorphism and long-term survival in patients with idiopathic congestive heart failure. Eur J Heart Fail 1: 363-369, 1999.
    OpenUrlCrossRefPubMed
  103. 104.↵
    1. Hamon M,
    2. Amant C,
    3. Bauters C,
    4. Richard F,
    5. Helbecque N,
    6. McFadden EP,
    7. Lablanche JM,
    8. Bertrand M,
    9. Amouyel P
    : Association of angiotensin-converting enzyme and angiotensin II type 1 receptor genotypes with left ventricular function and mass in patients with angiographically normal coronary arteries. Heart 77: 489-490, 1997.
    OpenUrlFREE Full Text
  104. 105.↵
    1. Gruchala M,
    2. Ciecwierz D,
    3. Ochman K,
    4. Wasag B,
    5. Koprowski A,
    6. Wojtowicz A,
    7. Dubaniewicz W,
    8. Targonski R,
    9. Sobiczewski W,
    10. Grzybowski A,
    11. Grzybowski A,
    12. Romanowski P,
    13. Limon J,
    14. Rynkiewicz A
    : Left ventricular size, mass and function in relation to angiotensin-converting enzyme gene and angiotensin-II type 1 receptor gene polymorphisms in patients with coronary artery disease. Clin Chem Lab Med 41: 522-528, 2003.
    OpenUrlCrossRefPubMed
  105. 106.↵
    1. Wolf G
    : The road not taken: role of angiotensin II type 2 receptor in pathophysiology. Nephrol Dial Transplant 17: 195-198, 2002.
    OpenUrlFREE Full Text
  106. 107.↵
    1. Stoll M,
    2. Steckelings UM,
    3. Paul M,
    4. Bottari SP,
    5. Metzger R,
    6. Unger T
    : The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest 95: 651-657, 1995.
    OpenUrlCrossRefPubMed
  107. 108.↵
    1. Pucell AG,
    2. Hodges JC,
    3. Sen I,
    4. Bumpus FM,
    5. Husain A
    : Biochemical properties of the ovarian granulosa cell type 2-angiotensin II receptor. Endocrinology 128: 1947-1959, 1991 (abstract).
    OpenUrlCrossRefPubMed
  108. 109.
    1. Dudley DT,
    2. Summerfelt RM
    : Regulated expression of angiotensin II (AT2) binding sites in R3T3 cells. Regul Pept 44: 199-206, 1993.
    OpenUrlCrossRefPubMed
  109. 110.↵
    1. Ouali R,
    2. Berthelon MC,
    3. Bégeot M,
    4. Saez JM
    : Angiotensin II receptor subtypes AT1 and AT2 are down-regulated by angiotensin II through AT1 receptor by different mechanisms. Endocrinology 138: 725-733, 1997.
    OpenUrlCrossRefPubMed
  110. 111.↵
    1. Williams GH,
    2. Moore TJ,
    3. Hollenberg NK
    : Dysregulation of aldosterone secretion and its relationship to the pathogenesis of essential hypertension. Endocrinol Metab Clin North America 20: 423-447, 1991.
    OpenUrl
  111. 112.↵
    1. Refaat S,
    2. El-Ghaffar NA,
    3. El-Rahman Negm HA,
    4. Yousri T
    : The role of aldosterone in myocardial dysfunction of Egyptian patients with essential hypertension. Arch Med Sci 4: 161-166, 2008.
    OpenUrl
  112. 113.↵
    1. Cohn JN,
    2. Colucci W
    : Cardiovascular effects of aldosterone and post-acute myocardial infarction pathophysiology. Am Cardiol 97: 4-12, 2006.
    OpenUrl
  113. 114.↵
    1. Donderski R,
    2. Grajewska M,
    3. Manitius J
    : Aldosteron i jego znaczenie w uszkodzeniu ukladu sercowo-naczyniowego u osób z przewleklą chorobą nerek. Kardiol Pol 64: 423-427, 2006.
    OpenUrlPubMed
  114. 115.↵
    1. Schiffrin EL
    : Wplyw aldosteronu na naczynia. Hypertension (Polish edition) 2: 1-7, 2006.
    OpenUrl
  115. 116.↵
    1. Hyla-Klekot L,
    2. Pulcer B,
    3. Kokot F
    : Uklad renina-angiotensyna-aldosteron- nowe aspekty patogenetyczne i lecznicze. Część 2. Aldosteron - ważny induktor szlaków patogenetycznych uszkadzających uklad sercowo-naczyniowy i nerki. Nadcisn Tętn 11: 357-363, 2007.
    OpenUrl
  116. 117.↵
    1. Sutton MG,
    2. Sharpe N
    : Left ventricular remodeling after myocardial infarction pathophysiology and therapy. Circulation 101: 2981-2988, 2000.
    OpenUrlFREE Full Text
  117. 118.↵
    1. Ahokas RA,
    2. Warrington KJ,
    3. Gerling IC,
    4. Sun Y,
    5. Wodi LA,
    6. Herring P,
    7. Lu L,
    8. Bhattacharya SK,
    9. Postlethwaite AE,
    10. Weber KT
    : Aldosteronism and peripheral blood mononuclear cell activation: a neuroendocrine-immune interface. Circ Res 93: e124-e135, 2003.
    OpenUrlCrossRefPubMed
  118. 119.↵
    1. Marumo T,
    2. Uchimura H,
    3. Hayashi M,
    4. Hishikawa K,
    5. Fujita T
    : Aldosterone impairs bone marrow-derived progenitor cell formation. Hypertension 48: 490-496, 2006.
    OpenUrlAbstract/FREE Full Text
  119. 120.↵
    1. Kara-Perz,
    2. Kosicka T,
    3. Gluszek J
    : Rola aldosteronu i antagonistów receptorów aldosteronu w chorobach ukladu sercowo-naczyniowego. Przewodnik Lekarza 7: 98-102, 2004.
    OpenUrl
  120. 121.↵
    1. Ouvrard-Pascaud A,
    2. Sainte-Marie Y,
    3. Bénitah JP,
    4. Perrier R,
    5. Soukaseum C,
    6. Cat AN,
    7. Royer A,
    8. Le Quang K,
    9. Charpentier F,
    10. Demolombe S,
    11. Mechta-Grigoriou F,
    12. Beggah AT,
    13. Maison-Blanche P,
    14. Oblin ME,
    15. Delcayre C,
    16. Fishman GI,
    17. Farman N,
    18. Escoubet B,
    19. Jaisser F
    : Conditional mineralocorticoid receptor expression in the heart leads to life-threatening arrhythmias. Circulation 111: 3025-3033, 2005.
    OpenUrlAbstract/FREE Full Text
  121. 122.↵
    1. Qin W,
    2. Rudolph AE,
    3. Bond BR,
    4. Rocha R,
    5. Blomme EA,
    6. Goellner JJ,
    7. Funder JW,
    8. McMahon EG
    : Transgenic model of aldosterone-driven cardiac hypertrophy and heart failure. Circ Res 93: 69-76, 2003.
    OpenUrlAbstract/FREE Full Text
  122. 123.↵
    1. Biondi-Zoccai GG,
    2. Abbate A,
    3. Baldi A
    : Potential antiapoptotic activity of aldosterone antagonists in postinfarction remodeling [letter]. Circulation 108: e26, 2003.
    OpenUrlPubMed
  123. 124.↵
    1. Kupari M,
    2. Hautanen A,
    3. Lankinen I,
    4. Koskinen P,
    5. Virolainen J,
    6. Nikkila H,
    7. White PC
    : Associations between human aldosterone synthase (CYP11B2) gene polymorphisms and left ventricular size, mass, and function. Circulation 97: 569-575, 1998.
    OpenUrlAbstract/FREE Full Text
  124. 125.↵
    1. White PC,
    2. Slutsker L
    : Haplotype analysis of CYP11B2. Endocr Res 21: 437-442, 1995.
    OpenUrlCrossRefPubMed
  125. 126.↵
    1. Davies E,
    2. Holloway CD,
    3. Ingram MC,
    4. Inglis GC,
    5. Friel EC,
    6. Morrison C,
    7. Anderson NH,
    8. Fraser R,
    9. Connell JMC
    : Aldosterone excretion rate and blood pressure in essential hypertension are related to polymorphic differences in the aldosterone synthase gene CYP11B2. Hypertension 33: 703-707, 1999.
    OpenUrlAbstract/FREE Full Text
  126. 127.↵
    1. Lala DS,
    2. Rice DA,
    3. Parker KL
    : Steroidogenic factor I, a key regulator of steroidogenic enzyme expression, is the mouse homolog of fushi tarazu-factor I. Mol Endocrinol 6: 1249-1258, 1992.
    OpenUrlCrossRefPubMed
  127. 128.↵
    1. Tamaki S,
    2. Iwai N,
    3. Tsujita Y,
    4. Kinoshita M
    : Genetic polymorphism of CYP11B2 gene and hypertension in Japanese. Hypertension 33: 266-270, 1999.
    OpenUrlAbstract/FREE Full Text
  128. 129.↵
    1. Klimov AN,
    2. Gurevich VS,
    3. Nikiforova AA,
    4. Shatilina LV,
    5. Kuzmin AA,
    6. Plavinsky SL,
    7. Teryukova NP
    : Antioxidative activity of high density lipoprotein in vivo. Atheriosclerosis 100: 13-18, 1993.
    OpenUrl
  129. 130.↵
    1. Kelso GJ,
    2. Stuart WD,
    3. Richter RJ,
    4. Furlong CE,
    5. Jordan-Starck TC,
    6. Harmony AK
    : Apolipoprotein J is associated with paraoxonase in human plasma. Biochemistry 33: 832-839, 1994.
    OpenUrlCrossRefPubMed
  130. 131.↵
    1. Filippatos TD,
    2. Tsimihodimos V,
    3. Kostapanos M,
    4. Kostara C,
    5. Bairaktari ET,
    6. Kiortsis DN,
    7. Tselepis AD,
    8. Elisaf MS
    : Small dense LDL cholesterol and apolipoproteins C-II and C-III in non-diabetic obese subjects with metabolic syndrome. Arch Med Sci 4: 263-269, 2008.
    OpenUrl
  131. 132.↵
    1. Primo-Parmo SL,
    2. Hsu C,
    3. Law DJ,
    4. La Du BN
    : Location and arrangement of three paraoxonase genes: PON1, PON2 and PON3, on human chromosome 7. Am J Hum Genet suppl 59: A406, 1996.
    OpenUrl
  132. 133.↵
    1. Guxens M,
    2. Tomas M,
    3. Elosua R,
    4. Aldasoro E,
    5. Segura A,
    6. Fiol M,
    7. Sala J,
    8. Vila J,
    9. Fullana M,
    10. Sentí M,
    11. Vega G,
    12. de la Rica M,
    13. Marrugat J,
    14. investigadores del estudio IBERICA
    : Association between paraoxonase-1 and paraoxonase-2 polymorphisms and the risk of acute myocardial infarction. Rev Esp Cardiol 61: 269-275, 2008.
    OpenUrlCrossRefPubMed
  133. 134.↵
    1. Ng CJ,
    2. Wadleigh DJ,
    3. Gangopadhyay A,
    4. Hama S,
    5. Grijalva VR,
    6. Navab M,
    7. Fogelman AM,
    8. Reddy ST
    : Paraoxonase-2 is a ubiquitously expressed protein with antioxidant properties and is capable of preventing cell-mediated oxidative modification of low density lipoprotein. J Biol Chem 276: 44444-44449, 2001.
    OpenUrlAbstract/FREE Full Text
  134. 135.↵
    1. Watson AD,
    2. Berlinor JA,
    3. Hama SY,
    4. La Du BN,
    5. Faull KF,
    6. Fogelman AM,
    7. Navab M
    : Protective effect of high density lipoprotein associated paraoxonase: inhibition of the biological activity of minimally oxidized low density lipoprotein. J Clin Invest 96: 2882-2891, 1995.
    OpenUrlCrossRefPubMed
  135. 136.↵
    1. Aviram M,
    2. Rosenblat M,
    3. Bisgaier CL,
    4. Newton SL,
    5. Primo-Parmo SL,
    6. La Du BN
    : Paroxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative role for paraoxonase. J Clin Invest 101: 1581-1590, 1998.
    OpenUrlCrossRefPubMed
  136. 137.↵
    1. Rosenblat M,
    2. Gaidukov L,
    3. Khersonsky O,
    4. Vaya J,
    5. Oren R,
    6. Tawfik DS
    : The catalytic histidine dyad of high density lipoprotein-associated serum paraoxonase-1 (PON1) is essential for PON1-mediated inhibition of low density lipoprotein oxidation and stimulation of macrophage cholesterol efflux. J Biol Chem 281: 7657-7665, 2006.
    OpenUrlAbstract/FREE Full Text
  137. 138.↵
    1. La Du BN
    : Is paraoxonase-3 another HDL-associated protein protective against atherosclerosis? Arterioscler, Thromb Vasc Biol 21: 467-468, 2001.
    OpenUrlFREE Full Text
  138. 139.
    1. Robertson KS,
    2. Hawe E,
    3. Miller GJ,
    4. Talmud PJ,
    5. Humphries SE
    : Human paraoxonase gene cluster polymorphisms as predictors of coronary heart disease risk in the prospective Northwick Park Heart Study II. Biochim Biophys Acta 1639: 203-212, 2003.
    OpenUrlPubMed
  139. 140.↵
    1. Jakubowski H
    : Calcium-dependent human serum homocysteine thiolactone hydrolase: a protective mechanism against protein N-homocysteinylation. J Biol Chem 275: 3957-3962, 2000.
    OpenUrlAbstract/FREE Full Text
  140. 141.↵
    1. Mackness B,
    2. Durrington P,
    3. McElduff P,
    4. Yarnell J,
    5. Azam N,
    6. Watt M,
    7. Mackness M
    : Low paraoxonase activity predicts coronary events in the Caerphilly prospective study. Circulation 107: 2775-2779, 2003.
    OpenUrlAbstract/FREE Full Text
  141. 142.↵
    1. Mackness B,
    2. Davies GK,
    3. Turkie W,
    4. Lee E,
    5. Roberts DH,
    6. Hill E,
    7. Roberts C,
    8. Durrington PN,
    9. Mackness MI
    : Paraoxonase status in coronary heart disease are activity and concentration more important than genotype? Arterioscler Thromb Vasc Biol 21: 1451-1457, 2001.
    OpenUrlAbstract/FREE Full Text
  142. 143.↵
    1. Ruiz J,
    2. Blanche H,
    3. James RW,
    4. Garin MCB,
    5. Vaisse C,
    6. Charpentier G,
    7. Cohen N,
    8. Morabia A,
    9. Passa P,
    10. Froguel P
    : Gln-Arg 192 polymorphism of paraoxonase and coronary heart disease in type 2 diabetes. Lancet 346: 869-872, 1995.
    OpenUrlCrossRefPubMed
  143. 144.
    1. Odawara M,
    2. Tachi Y,
    3. Yamashita K
    : Paraoxonase polymorphism (Gln192-Arg) is associated with coronary heart disease in Japanese noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 82: 2257-2260, 1997.
    OpenUrlCrossRefPubMed
  144. 145.↵
    1. Sanghera DK,
    2. Aston CE,
    3. Saha N,
    4. Kamboh MI
    : DNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary heart disease. Am J Hum Genet 62: 36-44, 1998.
    OpenUrlCrossRefPubMed
  145. 146.↵
    1. Ombres D,
    2. Pannitteri G,
    3. Montali A,
    4. Candeloro A,
    5. Seccareccia F,
    6. Campagna F,
    7. Cantini R,
    8. Campa PP,
    9. Ricci G,
    10. Arca M
    : The Gln/Arg192 polymorphism of human paraoxonase gene is not associated with coronary artery disease in Italian patients. Arterioscler Thromb Vasc Biol 18: 1611-1616, 1998.
    OpenUrlAbstract/FREE Full Text
  146. 147.↵
    1. Gardemann A,
    2. Philipp M,
    3. Heß K,
    4. Katz N,
    5. Tillmanns H,
    6. Haberbosch W
    : The paraoxonase Leu-Met54 and Gln-Arg191 gene polymorphisms are not associated with the risk of coronary heart disease. Atherosclerosis 152: 421-431, 2000.
    OpenUrlPubMed
  147. 148.↵
    1. Nakanishi M,
    2. Takanami Y,
    3. Maruyama T,
    4. Murata M,
    5. Motohashi Y,
    6. Nakano S,
    7. Uchida K,
    8. Maruyama C,
    9. Kyotani S,
    10. Tsushima Motoo
    : The ratio of serum paraoxonase/arylesterase activity an improved assay for arylesterase activity to discriminate PON1 R192 from PON1 Q192. J Atheroscler Thromb 10: 337-342, 2003.
    OpenUrlPubMed
  148. 149.↵
    1. Mackness MI,
    2. Arrol S,
    3. Mackness B,
    4. Durrington PN
    : Alloenzymes of paraoxonase and effectiveness of high-density lipoprotein in protecting low density lipoprotein against lipid peroxidation. Lancet 349: 851-852, 1997.
    OpenUrlCrossRefPubMed
  149. 150.↵
    1. Jarvik GP,
    2. Jampsa R,
    3. Richter RJ,
    4. Carlson CS,
    5. Rieder MJ,
    6. Nickerson DA,
    7. Furlong CE
    : Novel paraoxonase (PON1) nonsense and missense mutations predicted by functional genomic assay of PON1 status. Pharmacogenetics 13: 291-295, 2003.
    OpenUrlCrossRefPubMed
  150. 151.↵
    1. Mackness B,
    2. Mackness MI,
    3. Arrol S,
    4. Turkie W,
    5. Durrington PN
    : Effect of the human serum paraoxonase 55 and 192 genetic polymorphisms on the protection by high density lipoprotein against low density lipoprotein oxidative modification. FEBS Letters 423: 57-60, 1998.
    OpenUrlCrossRefPubMed
  151. 152.↵
    1. Durrington P,
    2. Mackness B,
    3. Mackness MI
    : Paraoxonase and atherosclerosis. Arterioscler Thromb Vasc Biol 21: 473-480, 2001.
    OpenUrlAbstract/FREE Full Text
  152. 153.↵
    1. Shih DM,
    2. Gu L,
    3. Xia YR,
    4. Navab M,
    5. Hamal S,
    6. Castellani LW,
    7. Furlong CE,
    8. Costa LG,
    9. Fogelman AM,
    10. Lusis AJ
    : Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. Nature 394: 284-287, 1998.
    OpenUrlCrossRefPubMed
  153. 154.↵
    1. Martinelli N,
    2. Girelli D,
    3. Olivieri O,
    4. Stranieri C,
    5. Trabetti E,
    6. Pizzolo F,
    7. Friso S,
    8. Tenuti I,
    9. Cheng S,
    10. Grow MA,
    11. Pignatti PF,
    12. Corrocher R
    : Interaction between smoking and PON2 Ser311Cys polymorphism as a determinant of the risk of myocardial infarction. Eur J Clin Invest 34: 14-20, 2004.
    OpenUrlCrossRefPubMed
  154. 155.↵
    1. Chen Q,
    2. Reis SE,
    3. Kammerer CM,
    4. McNamara DM,
    5. Holubkov R,
    6. Sharaf BL,
    7. Sopko G,
    8. Pauly DF,
    9. Merz CNB,
    10. Kamboh MI,
    11. the WISE Study Group
    : Association between the severity of angiographic coronary artery disease and paraoxonase gene polymorphisms in the National Heart, Lung and Blood Institute - sponsored women's ischemia syndrome evaluation (WISE) study. Am J Hum Genet 72: 13-22, 2003.
    OpenUrlCrossRefPubMed
  155. 156.↵
    1. Roy AC,
    2. Saha N,
    3. Tay JSH,
    4. Ratnam SS
    : Serum paraoxonase polymorphism in three populations of Southeast Asia. Hum Hered 141: 265-269, 1991.
    OpenUrlCrossRef
  156. 157.↵
    1. Jarvik GP,
    2. Rozek LS,
    3. Brophy VH,
    4. Hatsukami TS,
    5. Richter RJ,
    6. Schellenberg GD,
    7. Furlong CE
    : Paraoxonase (PON1) phenotype is a better predictor of vascular disease than is PON1 192 or PON1 55 genotype. Arterioscler Thromb Vasc Biol 20: 2441-2447, 2000.
    OpenUrlAbstract/FREE Full Text
  157. 158.↵
    1. Piechota M,
    2. Banach M,
    3. Jacoń A,
    4. Rysz J
    : Natriuretic peptides in cardiovascular diseases. Cell Mol Biol Lett 13: 155-181, 2008.
    OpenUrlPubMed
  158. 159.↵
    1. Vita JA
    : Endothelial function and clinical outcome (abstract). Heart 91: 1278-1279, 2005.
    OpenUrlFREE Full Text
  159. 160.↵
    1. Agapitov AV,
    2. Haynes WG
    : Role of endothelin in cardiovascular disease. J Renin Angiotensin Aldosterone Syst 3: 1-15, 2002.
    OpenUrlAbstract/FREE Full Text
  160. 161.↵
    1. Yanagisawa M,
    2. Kurihawa H,
    3. Kimura S
    : A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332: 411-415, 1988.
    OpenUrlCrossRefPubMed
  161. 162.↵
    1. Hosoda K,
    2. Nakao K,
    3. Hiroshi-Arai,
    4. Suga S,
    5. Ogawa Y,
    6. Mukoyama M,
    7. Shirakami G,
    8. Saito Y,
    9. Nakanishi S,
    10. Imura H
    : Cloning and expression of human endothelin-1 receptor cDNA. FEBS Lett 287: 23-26, 1991.
    OpenUrlCrossRefPubMed
  162. 163.↵
    1. Ogawa Y,
    2. Nakao K,
    3. Arai H
    . Molecular cloning of a nonisopeptide-selective human endothelin receptor. Biochem Biophys Res Commun 178: 248-255, 1991.
    OpenUrlCrossRefPubMed
  163. 164.↵
    1. Spieker LE,
    2. Noll G,
    3. Ruschitzka FT,
    4. Lüscher TF
    : Endothelin receptor antagonists in congestive heart failure: a new therapeutic principle for the future. J Am Coll Cardiol 37: 1493-1505, 2001.
    OpenUrlCrossRefPubMed
  164. 165.↵
    1. Aydin U,
    2. Ugurlucan M,
    3. Gungor F,
    4. Ziyade S,
    5. Inan B,
    6. Banach M,
    7. Kalko Y,
    8. Yasar T
    : Effects of atorvastatin on vascular intimal hyperplasia: an experimental rodent model. Angiology, 2009.
  165. 166.↵
    1. Kohno M,
    2. Yokokawa K,
    3. Yasunari K,
    4. Kano H,
    5. Minami M,
    6. Yoshikawa J
    : Effect of the endothelin family of peptides on human coronary artery smooth-muscle cell migration. J Cardiovasc Pharmacol 31: S84-S89, 1998.
    OpenUrlCrossRefPubMed
  166. 167.↵
    1. Jagroop IA,
    2. Daskalopoulou SS,
    3. Mikhailidis DP
    : Endothelin-1 and human platelets. Curr Vasc Pharmacol 3: 393-399, 2005.
    OpenUrlCrossRefPubMed
  167. 168.↵
    1. Irzmański R,
    2. Banach M,
    3. Piechota M,
    4. Kowalski J,
    5. Barylski M,
    6. Cierniewski C,
    7. Pawlicki L
    : Atrial and brain natriuretic peptide and endothelin-1 concentration in patients with idiopathic arterial hypertension: the dependence on the selected morphological parameters. Clin Exp Hypertens 29: 149-164, 2007.
    OpenUrlCrossRefPubMed
  168. 169.↵
    1. Negrusz-Kawecka M
    : Udzial endotelin w schorzeniach ukladu krążenia. Pol Merk Lek 11: 444-446, 2001.
    OpenUrl
  169. 170.↵
    1. Miyauchi T,
    2. Yanagisawa M,
    3. Tomizawa T,
    4. Sugishita Y,
    5. Suzuki N,
    6. Fujino M,
    7. Ajisaka R,
    8. Goto K,
    9. Masaki T
    : Increased plasma concentrations of endothelin-1 and big endothelin-1 in acute myocardial infarction. Lancet 2: 54, 1989.
    OpenUrlPubMed
  170. 171.↵
    1. Nessler J,
    2. Piwowarska W,
    3. Nessler B,
    4. Kitliński M,
    5. Mroczek-Czernecka D,
    6. Stępniewski M
    : Stężenie endoteliny 1 (ET-1) u chorych z niewydolnością serca o etiologii niedokrwiennej. Folia Cardiol 10: 169-175, 2003.
    OpenUrl
  171. 172.↵
    1. Ihara M,
    2. Noguchi K,
    3. Saeki T,
    4. Fukuroda T,
    5. Tsuchida S,
    6. Kimura S,
    7. Fukami T,
    8. Ishikawa K,
    9. Nishikibe M,
    10. Yano M
    : Biological profiles of highly potent novel endothelin antagonists selective for the ETA receptor. Life Sci 50: 247-255, 1992.
    OpenUrlCrossRefPubMed
  172. 173.↵
    1. Tiret L,
    2. Poirier O,
    3. Hallet V,
    4. McDonagh TA,
    5. Morrison C,
    6. McMuray JJ,
    7. Dargie HJ,
    8. Arveiler D,
    9. Ruidavets JB,
    10. Luc G,
    11. Evans A,
    12. Cambien F
    : The Lys198Asn polymorphism in the endothelin-1 gene is associated with blood pressure in overweight people. Hypertension 33: 1169-1174, 1999.
    OpenUrlAbstract/FREE Full Text
  173. 174.↵
    1. Iglarz M,
    2. Benessiano J,
    3. Philip I,
    4. Vuillaumier-Barrot S,
    5. Lasocki S,
    6. Hvass U,
    7. Durand G,
    8. Desmonts JM,
    9. Lévy BI,
    10. Henrion D
    : Preproendothelin-1 gene polymorphism is related to a change in vascular reactivity in the human mammary artery in vitro. Hypertension 39: 209-213, 2002.
    OpenUrlAbstract/FREE Full Text
  174. 175.↵
    1. Asai T,
    2. Ohkubo T,
    3. Katsuya T,
    4. Higaki J,
    5. Fu Y,
    6. Fukuda M,
    7. Hozawa A,
    8. Matsubara M,
    9. Kitaoka H,
    10. Tsuji I,
    11. Araki T,
    12. Satoh H,
    13. Hisamichi S,
    14. Imai Y,
    15. Ogihara T
    : Endothelin-1 gene variant associates with blood pressure in obese Japanese subjects: the Ohasama Study. Hypertension 38: 1321-1324, 2001.
    OpenUrlAbstract/FREE Full Text
  175. 176.↵
    1. Colombo MG,
    2. Ciofini E,
    3. Paradossi U,
    4. Bevilacqua S,
    5. Biagini A
    . ET-1 Lys198Asn and ET(A) receptor H323H polymorphisms in heart failure. A case-control study. Cardiology 105: 246-252, 2006.
    OpenUrlCrossRefPubMed
  176. 177.↵
    1. Antoniades C,
    2. Tousoulis D,
    3. Vasiliadou C,
    4. Pitsavos C,
    5. Chrysochoou C,
    6. Panagiotakos D,
    7. Tentolouris C,
    8. Marinou K,
    9. Koumallos N,
    10. Stefanadis C
    : Genetic polymorphism on endothelial nitric oxide synthase affects endothelial activation and inflammatory response during the acute phase of myocardial infarction. (Abstract). J Am Coll Cardiol 46: 1101-1109, 2005.
    OpenUrlCrossRefPubMed
  177. 178.↵
    1. Ignarro LJ
    : Physiology and pathophysiology of nitric oxide. Kidney Int (Suppl.) 55: 2-5, 1996.
    OpenUrl
  178. 179.↵
    1. Loscalzo J,
    2. Welch G
    : Nitric oxide and its role in the cardiovascular system. Prog Cardiovasc Dis 38: 87-104, 1995.
    OpenUrlCrossRefPubMed
  179. 180.↵
    1. Schmidt HHHW,
    2. Walter U
    : NO at work. Cell 78: 919-925, 1994.
    OpenUrlCrossRefPubMed
  180. 181.↵
    1. Huang PL,
    2. Huang Z,
    3. Mashimo H
    : Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 377: 239-242, 1995.
    OpenUrlCrossRefPubMed
  181. 182.↵
    1. Irokawa M,
    2. Nishinaga M,
    3. Funayama H,
    4. Shimada K
    : The effect of endothelium-derived relaxing factor (EDRF) on anticoagulant heparan sulfate on cultured vascular endothelial cell (EC). Circulation 90: I-396, 1994.
    OpenUrl
  182. 183.↵
    1. Morray B,
    2. Goldenberg I,
    3. Moss AJ,
    4. Zareba W,
    5. Ryan D,
    6. McNitt S,
    7. Eberly SW,
    8. Glazko G,
    9. Mathew J
    : Polymorphisms in the paraoxonase and endothelial nitric oxide synthase genes and the risk of early-onset myocardial infarction. Am J Cardiol 99: 1100-1105, 2007.
    OpenUrlCrossRefPubMed
  183. 184.↵
    1. Ross R
    : Atherosclerosis - an inflammatory disease. Nature 340: 115-126, 1999.
    OpenUrl
  184. 185.↵
    1. Schächinger V,
    2. Zeiher AM
    : Atherogenesis-recent insights into basic mechanisms and their clinical impact. Nephrol Dial Transplant 17: 2055-2064, 2002.
    OpenUrlFREE Full Text
  185. 186.↵
    1. Cook S
    : Coronary artery disease, nitric oxide and oxidative stress: the ‘Yin-Yang’ effect - a Chinese concept for a worldwide pandemic. Swiss Med Wkly 136: 103-113, 2006.
    OpenUrlPubMed
  186. 187.↵
    1. Lee CR,
    2. North KE,
    3. Bray MS,
    4. Avery CL,
    5. Mosher MJ,
    6. Couper DJ,
    7. Coresh J,
    8. Folsom AR,
    9. Boerwinkle E,
    10. Heiss G,
    11. Zeldin DC
    : NOS3 polymorphisms, cigarette smoking, and cardiovascular disease risk: The Atherosclerosis Risk in Communities study. Pharmacogenet Genomics 16: 891-899, 2006.
    OpenUrlCrossRefPubMed
  187. 188.↵
    1. Guzik TJ,
    2. Black E,
    3. West NE
    : Relationship between the G894T polymorphism (Glu 298Asp variant) in endothelial nitric oxide synthase and nitric oxide mediated endothelial function in human atherosclerosis. Am J Med Genet 100: 130-137, 2001.
    OpenUrlCrossRefPubMed
  188. 189.↵
    1. Naruse K,
    2. Shimizu K,
    3. Muramatsu M,
    4. Toki Y,
    5. Miyazaki Y,
    6. Okumura K,
    7. Hashimoto H,
    8. Ito T
    : Long-term inhibition of NO synthesis promotes atherosclerosis in hypercholesterolemic rabbit thoracic aorta: PGH2 does not contribute to impared endothelium-dependent relaxation. Arterioscler Thromb Vasc Biol 14: 746-752, 1994.
    OpenUrlAbstract/FREE Full Text
  189. 190.↵
    1. Cayatte A,
    2. Palacino J,
    3. Horten K,
    4. Cohen RA
    : Chronic inhibition of nitric oxide production accelerates neointima formation and impairs endothelial function in hypercholesterolaemic rabbits. Arterioscler Thromb Vasc Biol 14: 753-759, 1994.
    OpenUrlAbstract/FREE Full Text
  190. 191.↵
    1. Cattaruzza M,
    2. Guzik TJ,
    3. Slodowski W
    : Shear stress insensitivity of endothelial nitric oxide synthase expression as a genetic risk factor for coronary heart disease. Circ Res 95: 841-847, 2004.
    OpenUrlAbstract/FREE Full Text
  191. 192.↵
    1. Jeerooburkhan N,
    2. Jones LC,
    3. Bujac S,
    4. Cooper JA,
    5. Miller GJ,
    6. Vallance P,
    7. Humphries SE,
    8. Hingorani AD
    : Genetic and environmental determinants of plasma nitrogen oxides and risk of ischemic heart disease. Hypertension 38: 1054-1061, 2001.
    OpenUrlAbstract/FREE Full Text
  192. 193.
    1. Hingorani AD,
    2. Jia H,
    3. Stevens PA,
    4. Monteith MS,
    5. Brown MJ
    : A common variant in exon 7 of the endothelial constitutive nitric oxide synthase gene. Clin Sci 88: 21P, 1995.
    OpenUrlFREE Full Text
  193. 194.
    1. Poirier O,
    2. Mao C,
    3. Mallet C,
    4. Nicaud V,
    5. Herrmann S M,
    6. Evans A,
    7. Ruidavets JB,
    8. Arveiler D,
    9. Luc G,
    10. Tiret L,
    11. Soubrier F,
    12. Cambien F
    : Polymorphisms of the endothelial nitric oxide synthase gene: no consistent association with myocardial infarction in ECTIM study. Eur J Clin Invest 29: 284-290, 1999.
    OpenUrlCrossRefPubMed
  194. 195.↵
    1. Bonnardeaux A,
    2. Nadaud S,
    3. Charru A,
    4. Jeunemaitre X,
    5. Corvol P,
    6. Soubrier F
    : Lack of evidence for linkage of the endothelial cell nitric oxide synthase gene to essential hypertension. Circulation 91: 96-102, 1995.
    OpenUrlAbstract/FREE Full Text
  195. 196.↵
    1. Rios DL,
    2. Callegari-Jacques SM,
    3. Hutz MH
    : Endothelial nitric oxide synthase and fractalkine chemokine receptor polymorphisms on angiographically assessed coronary atherosclerosis. Clin Chim Acta 362: 138-146, 2005.
    OpenUrlCrossRefPubMed
  196. 197.↵
    1. Alvarez R,
    2. Gonzales P,
    3. Batalla A,
    4. Reguero JR,
    5. Iglesias-Cubero G,
    6. Hevia S,
    7. Cortina A,
    8. Merino E,
    9. González I,
    10. Alvarez V,
    11. Coto E
    : Association between the NOS3 (786T/C) and the ACE (I/D) DNA genotypes and early coronary artery disease. Nitric Oxide 5: 343-349, 2001.
    OpenUrlCrossRefPubMed
  197. 198.↵
    1. Miyamoto Y,
    2. Yoshihiko S,
    3. Kajiyama M,
    4. Yoshimura M,
    5. Shimasaki Y,
    6. Nakayama M,
    7. Kamitani S,
    8. Harada M,
    9. Ishikawa M,
    10. Kuwahara K,
    11. Ogawa E,
    12. Hamanaka I,
    13. Takahashi N,
    14. Kaneshige T,
    15. Teraoka H,
    16. Akamizu T,
    17. Azuma N,
    18. Yoshimasa Y,
    19. Yoshimasa T,
    20. Itoh H,
    21. Masuda I,
    22. Yasue H,
    23. Nakao K
    : Endothelial nitric oxide synthase gene is positively associated with essential hypertension. Hypertension 32: 3-8, 1998.
    OpenUrlAbstract/FREE Full Text
  198. 199.↵
    1. Casas JP,
    2. Bautista LE,
    3. Humphries SE,
    4. Hingorani AD
    : Endothelial nitric oxide synthase genotype and ischemic heart disease: meta-analysis of 26 studies involving 23,028 subjects. Circulation 109: 1359-1365, 2004.
    OpenUrlAbstract/FREE Full Text
  199. 200.↵
    1. Yoshimura M,
    2. Yasue H,
    3. Nakayama M
    : Genetic risk factors for coronary artery spasm: significance of endothelial nitric oxide synthase gene T786C and missense Glu298Asp variants. J Investig Med 48: 367-374, 2000.
    OpenUrlPubMed
  200. 201.↵
    1. Gomma AH,
    2. Elrayess MA,
    3. Knight CJ,
    4. Hawe E,
    5. Fox KM,
    6. Humphries SE
    : The endothelial nitric oxide synthase (Glu298Asp and 786T/C) gene polymorphisms are associated with coronary in-stent restenosis. Eur Heart J 23: 1955-1962, 2002.
    OpenUrlAbstract/FREE Full Text
  201. 202.↵
    1. Tesauro M,
    2. Thompson WC,
    3. Rogliani P,
    4. Qi L,
    5. Chaudhary PP,
    6. Moss J
    : Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs. glutamate at position 298. Proc Natl Acad Sci USA 97: 2832-2835, 2000.
    OpenUrlAbstract/FREE Full Text
  202. 203.↵
    1. McDonald DM,
    2. Alp NJ,
    3. Channon KM
    : Functional comparison of the endothelial nitric oxide synthase Glu298Asp polymorphic variants in human endothelial cells. Pharmacogenetics 14: 831-839, 2004.
    OpenUrlCrossRefPubMed
  203. 204.↵
    1. Fairchild TA,
    2. Fulton D,
    3. Fontana JT,
    4. Gratton JP,
    5. McCabe TJ,
    6. Sessa WC
    : Acidic hydrolysis as a mechanism for the cleavage of the Glu(298)Asp variant of human endothelial nitric oxide synthase. J Biol Chem 276: 26674-26679, 2001.
    OpenUrlAbstract/FREE Full Text
  204. 205.↵
    1. Joshi MS,
    2. Mineo C,
    3. Shaul PW,
    4. Bauer JA
    : Biochemical consequences of the NOS3 Glu298Asp variation in human endothelium: altered caveolar localization and impaired response to shear. FASEB J 21: 2655-2663, 2007.
    OpenUrlAbstract/FREE Full Text
  205. 206.↵
    1. Busconi L,
    2. Michel T
    : Endothelial nitric oxide synthase. N-terminal myristoylation determines subcellular localization. J Biol Chem 268: 8410-8413, 1993.
    OpenUrlAbstract/FREE Full Text
  206. 207.↵
    1. Agema WR,
    2. De Maat MP,
    3. Zwinderman AH,
    4. Kastelein JJ,
    5. Rabelink TJ,
    6. Van Boven AJ,
    7. Feskens EJ,
    8. Boer JM,
    9. van der Wall EE,
    10. Jukema JW
    : An integrated evaluation of endothelial constitutive nitric oxide synthase polymorphisms and coronary artery disease in men. Clin Sci 107: 255-261, 2004.
    OpenUrlAbstract/FREE Full Text
  207. 208.↵
    1. Lembo G,
    2. De Luca N,
    3. Battagli C,
    4. Iovino G,
    5. Aretini A,
    6. Musicco M,
    7. Frati G,
    8. Pompeo F,
    9. Vecchione C,
    10. Trimarco B
    : A Common variant of endothelial nitric oxide synthase (Glu298Asp) is an independent risk factor for carotid atherosclerosis. Stroke 32: 735-740, 2001.
    OpenUrlAbstract/FREE Full Text
  208. 209.↵
    1. Nakayama M,
    2. Yasue H,
    3. Yoshimura M
    : T-786C mutation in the 5’-flanking region of the enothelial nitric oxide synthase gene is associated with coronary spasm. Circulation 99: 2864-2870, 1999.
    OpenUrlAbstract/FREE Full Text
  209. 210.↵
    1. Miyamoto Y,
    2. Saito Y,
    3. Nakayama M
    : Replication protein A1 reduces transcription of the endothelial nitric oxide synthase gene containing a -786T/C mutation associated with coronary spastic angina. Hum Mol Genet 9: 2629-2637, 2000.
    OpenUrlAbstract/FREE Full Text
  210. 211.↵
    1. Rossi GP,
    2. Cesari M,
    3. Zanchetta M,
    4. Colonna S,
    5. Maiolino G,
    6. Pedon L,
    7. Cavallin M,
    8. Maiolino P,
    9. Pessina AC
    : The T-786C endothelial nitric oxide synthase genotype is a novel risk factor for coronary artery disease in Caucasian patients of the GENICA study. J Am Coll Cardiol 41: 930-937, 2003.
    OpenUrlCrossRefPubMed
  211. 212.
    1. Rossi GP,
    2. Taddei S,
    3. Virdis A,
    4. Cavallin M,
    5. Ghiadoni L,
    6. Favilla S,
    7. Versari D,
    8. Sudano I,
    9. Pessina AC,
    10. Salvetti A
    : The T-786C and Glu298Asp polymorphisms of the endothelial nitric oxide gene affect the forearm blood flow responses of Caucasian hypertensive patients. J Am Coll Cardiol 41: 938-948, 2003.
    OpenUrlCrossRefPubMed
  212. 213.↵
    1. Colombo MG,
    2. Andreassi MG,
    3. Botto N,
    4. Manfredi S,
    5. Masetti S,
    6. Biagini A,
    7. Clerico A
    : Endothelial nitric oxide synthase gene polymorphisms and risk of coronary artery disease. Clin Chem 49: 389-395, 2003.
    OpenUrlAbstract/FREE Full Text
  213. 214.↵
    1. Yoon Y,
    2. Song J,
    3. Hong SH,
    4. Kim JQ
    : Plasma nitric oxide concentrations and nitric oxide synthase gene polymorphisms in coronary artery disease. Clin Chem 46: 1626-1630, 2000.
    OpenUrlAbstract/FREE Full Text
  214. 215.↵
    1. Derebecka N,
    2. Holysz M,
    3. Dankowski R,
    4. Wierzchowiecki M,
    5. Trzeciak WH
    : Polymorphism in intron 23 of the endothelial nitric oxide synthase gene (NOS3) is not associated with hypertension. Acta Biochimica Polonica 49: 263-268, 2008.
    OpenUrl
  215. 216.↵
    1. Nap A,
    2. Balt JC,
    3. Mathy MJ,
    4. van Zwieten PA
    : AT1-receptor blockade and sympathetic neurotransmission in cardiovascular disease. Autonomic Autacoid Pharmacol 23: 285-296, 2004.
    OpenUrl
  216. 217.↵
    1. Bristow MR
    : Beta-adrenergic receptor blockade in chronic heart failure. Circulation 101: 558-569, 2000.
    OpenUrlFREE Full Text
  217. 218.↵
    1. Francis GS,
    2. McDonald KM,
    3. Cohn JN
    : Neurohumoral activation in preclinical heart failure. Remodeling and the potential for intervention. Circulation 87 suppl 5: IV-90-IV-96, 1993.
    OpenUrl
  218. 219.↵
    1. Communal C,
    2. Sigh K,
    3. Pimental DR,
    4. Colucci WS
    : Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the β-adrenergic receptor. Circulation 98: 1329-1334, 1998.
    OpenUrlAbstract/FREE Full Text
  219. 220.↵
    1. Kozlowska H,
    2. Schlicker E,
    3. Kozlowski M,
    4. Siedlecka U,
    5. Laudański J,
    6. Malinowska B
    : Ligands at β2-, β3- and the low-affinity state of β1-adrenoceptors block the α1 adrenoceptor-mediated constriction in human pulmonary and rat mesenteric arteries. J Cardiovasc Pharmacol 46: 76-82, 2005.
    OpenUrlPubMed
  220. 221.↵
    1. White HL,
    2. Maqbool A,
    3. McMahon AD,
    4. Yates L,
    5. Ball SG,
    6. Hall AS,
    7. Balmorth A.J
    : An evaluation of the β1 adrenergic receptor Arg389Gly polymorphism in individuals at risk of coronary events. A WOSCOPS substudy. Eur Heart J 23: 1087-1092, 2002.
    OpenUrlAbstract/FREE Full Text
  221. 222.↵
    1. Metra M,
    2. Nodari S,
    3. D'Aloia A,
    4. Bontempi L,
    5. Boldi E,
    6. Cas LD
    : A rationale for the use of beta-blockers as standard treatment for heart failure. Am Heart J 139: 511-521, 2000.
    OpenUrlPubMed
  222. 223.
    1. Böhm M,
    2. Flesch M,
    3. Schnabel P
    : Beta-adrenergic signal transduction in the failing and hypertrophied myocardium. J Mol Med 75: 842-848, 1997.
    OpenUrlCrossRefPubMed
  223. 224.↵
    1. Lefkowitz RJ,
    2. Rockman HA,
    3. Koch WJ
    : Catecholamines, cardiac β adrenergic receptors, and heart failure. Circulation 101: 1634-1637, 2000.
    OpenUrlFREE Full Text
  224. 225.↵
    1. Eichhorn EJ,
    2. Bristow MR
    : Medical therapy can improve the biological properties of the chronically failing heart: a new era in the treatment of heart failure. Circulation 94: 2285-2296, 1996.
    OpenUrlAbstract/FREE Full Text
  225. 226.↵
    1. Biolol A,
    2. Rosal AS,
    3. Mazzottil NG,
    4. Martins S,
    5. Belló-Klein A,
    6. Rohde LE,
    7. Clausell N
    : The role of adrenergic receptor polymorphisms in heart failure. Braz J Med Biol Res 39: 1281-1290, 2006.
    OpenUrlPubMed
  226. 227.↵
    1. Mialet PJ,
    2. Rathz DA,
    3. Petrashevskaya NN,
    4. Hahn HS,
    5. Wagoner LE,
    6. Schwartz A,
    7. Dorn GW,
    8. Liggett SB
    : β1 Adrenergic receptor polymorphisms confer differential function and predisposition to heart failure. Nat Med 9: 1300-1305, 2003.
    OpenUrlCrossRefPubMed
  227. 228.↵
    1. Small KM,
    2. Wagoner LE,
    3. Levin AM,
    4. Kardia SLR,
    5. Liggett SB
    : Synergistic polymorphisms of β1 and α2C adrenergic receptors and the risk of congestive heart failure. N Engl J Med 347: 1135-1142, 2002.
    OpenUrlCrossRefPubMed
  228. 229.↵
    1. Brodde OE,
    2. Buscher R,
    3. Tellkamp R,
    4. Radke J,
    5. Dhein S,
    6. Insel PA
    : Blunted cardiac responses to receptor activation in subjects with Thr164Ile β2-adrenoreceptors. Circulation 103: 1048-1050, 2001.
    OpenUrlAbstract/FREE Full Text
  229. 230.↵
    1. Green SA,
    2. Cole G,
    3. Jacinto M,
    4. Innis M,
    5. Liggett SB
    : A polymorphism of the human β2 adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor. J Biol Chem 268: 23116-23121, 1993.
    OpenUrlAbstract/FREE Full Text
  230. 231.↵
    1. Turki J,
    2. Lorenz JN,
    3. Green SA,
    4. Donnelly ET,
    5. Jacinto M,
    6. Liggett SB
    : Myocardial signaling defects and impaired cardiac function of a human β2 adrenergic receptor polymorphism expressed in transgenic mice. Proc Natl Acad Sci USA 93: 10483-10488, 1996.
    OpenUrlAbstract/FREE Full Text
  231. 232.↵
    1. Liggett SB,
    2. Wagoner LE,
    3. Craft LL,
    4. Hornung RW,
    5. Hoit BD,
    6. McIntosh TC,
    7. Walsh RA
    : The Ile164 β2 adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. J Clin Invest 102: 1534-1539, 1998.
    OpenUrlCrossRefPubMed
  232. 233.↵
    1. Parker JD,
    2. Newton GE,
    3. Landzberg JS,
    4. Floras JS,
    5. Colucci WS
    : Functional significance of presynaptic α adrenergic receptors in failing and nonfailing human left ventricle. Circulation 92: 1793-1800, 1995.
    OpenUrlAbstract/FREE Full Text
  233. 234.↵
    1. Small KM,
    2. Forbes SL,
    3. Rahman FF,
    4. Bridges KM,
    5. Liggett SB
    : A four amino acid deletion polymorphism in the third intracellular loop of the human α2C adrenergic receptor confers impaired coupling to multiple effectors. J Biol Chem 275: 23059-23064, 2000.
    OpenUrlAbstract/FREE Full Text
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Genetic Determinants of Cardiovascular Disease: The Renin-Angiotensin-Aldosterone System, Paraoxonases, Endothelin-1, Nitric Oxide Synthase and Adrenergic Receptors
ANNA GLUBA, MACIEJ BANACH, DIMITRI P. MIKHAILIDIS, JACEK RYSZ
In Vivo Sep 2009, 23 (5) 797-812;
Reddit logo Twitter logo Facebook logo Mendeley logo

Jump to section