The cellular and molecular origin of reactive oxygen species generation during myocardial ischemia and reperfusion
Introduction
Coronary artery disease is the leading cause of death in North America and accounts for an estimated direct and indirect cost of over $448.5 billion (Rosamond et al., 2008). Less severe coronary artery disease can be treated pharmacologically or surgically without significant differences in outcomes (Mark et al., 1994, van Domburg et al., 2002), but coronary artery bypass grafting (CABG) reduces mortality among medium- and high-risk patients, including diabetics (Hoffman et al., 2003, BARI-Investigators, 2007), over non-surgical management (Yusuf et al., 1994) and percutaneous interventions (Hoffman et al., 2003, Rihal et al., 2003, Kuukasjarvi et al., 2006). The half-million annual CABG surgeries done in the United States alone testify to the effectiveness of this technique (Kozak et al., 2005).
Although the majority of patients undergoing surgical revascularization emerge without severe postoperative complications, a significant proportion of patients encounter conditions of impaired postoperative cardiac function. Patients with diabetes in particular have an elevated risk of cardiac complications after CABG, including low cardiac output syndrome (Rao et al., 1996, Yau et al., 1999, Brown et al., 2006), and accordingly have a lower 10-year survival (Brown et al., 2006). These patients are also two to five times more likely to develop cardiovascular disease and therefore account for up to 30% of open heart procedures (Scrutinio & Giannuzzi, 2008). Intraoperative ischemia-reperfusion injury is a major factor in the development of transient and prolonged postoperative cardiac dysfunction. Ischemia-reperfusion injury is derived from the reestablishment of sufficient oxygenated perfusion to ischemic tissues, and therefore extends past the realm of surgical revascularization to include thrombolytic and percutaneous interventions. A hallmark of myocardial reperfusion is the increased generation of reactive oxygen species, and these species are central mediators of ischemia-reperfusion injury.
Section snippets
Myocardial ischemia-reperfusion injury
During CABG with cardiopulmonary bypass (CPB), venous blood is redirected from the vena cava to the “heart–lung machine”, which mediates artificial gas exchange and pumps oxygenated blood back through the body via the aorta. The heart–lung machine provides the body with adequate perfusion through constant delivery of oxygenated blood downstream of the aorta, but cardiac perfusion is a direct physical consequence of cardiac systole/diastole cycling. Cardioplegia solution is administered through
Free-radical generation during myocardial ischemia and reperfusion
The concept that the reintroduction of molecular oxygen to the myocardium could induce a unique type of injury was first proposed by Hearse et al. in (1973) who noticed that a large fraction of cellular enzymes were released not during hypoxia, but rather upon sudden reoxygenation (Hearse et al., 1973). The concept was further supported when the inclusion of exogenous glucose to anoxic perfusate to supplement the limited endogenous myocardial supply was found to relieve cell injury at
Free radical-mediated damage during myocardial ischemia and reperfusion
The myocardium functions as a large interconnected electrical circuit in which synchronized diastole–systole cycling and contraction rely on coordinated conductivity during its component cardiomyocytes. Impaired heart function subsequent to ischemia and reperfusion is by extension a symptom of cell damage that regionally uncouples the myocardial conductivity network. The severity of cell damage incurred, which ranges from reversible to irreversible, is proportional to the magnitude of ROS
Protective strategies during cardiac surgery
The prevalence of coronary artery disease, combined with the lethality of its manifestations account for a major cause of death and disability worldwide. Stable atherosclerotic plaques result in chronic ischemia, which in turn leads to myocardial stunning, hibernation and remodeling anterograde of the plaque. These changes result in heart failure, and require revascularization to restore adequate cardiac performance. More urgently, unstable atherosclerotic plaques can rupture to yield coronary
Conclusion
Myocardial ischemia and reperfusion is a major source of cardiomyocyte injury within the context of a host of clinical pathologies. These pathologies include cardiac arrest, acute myocardial infarction, and low cardiac output syndrome after cardiac surgery. The financial and societal relevance of this type of injury is underscored by the increasing prevalence of heart disease. Any improvement in the clinical outcomes associated with these pathologies must be predicated on reducing the magnitude
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgments
This work is supported by the Canadian Institutes of Health Research Operating Grant #82757. Koen Raedschelders was the recipient of a Canada Graduate Scholarship from the Canadian Institutes of Health Research.
References (456)
- et al.
Superoxide dismutases-a review of the metal-associated mechanistic variations
Biochimica et Biophysica Acta
(2010) - et al.
Evidence that mitochondrial respiration is a source of potentially toxic oxygen free radicals in intact rabbit hearts subjected to ischemia and reflow
Journal of Biological Chemistry
(1993) - et al.
The relationship between plasma free 15-F2t-isoprostane concentration and early postoperative cardiac depression following warm heart surgery
The Journal of Thoracic and Cardiovascular Surgery
(2003) - et al.
Synchronized whole cell oscillations in mitochondrial metabolism triggered by a local release of reactive oxygen species in cardiac myocytes
Journal of Biological Chemistry
(2003) - et al.
Mitochondrial phospholipid hydroperoxide glutathione peroxidase plays a major role in preventing oxidative injury to cells
Journal of Biological Chemistry
(1999) - et al.
Identification of free radicals in myocardial ischemia/reperfusion by spin trapping with nitrone DMPO
FEBS Letters
(1987) - et al.
The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid
Free Radical Biology & Medicine
(1989) - et al.
Inflammatory response after coronary revascularization with or without cardiopulmonary bypass
The Annals of Thoracic Surgery
(2000) NADPH oxidase
Current Opinion in Immunology
(2004)- et al.
Modulation of the mitochondrial permeability transition pore. Effect of protons and divalent cations
Journal of Biological Chemistry
(1992)
A study of the reactivity of HO2/O2- with unsaturated fatty acids
Journal of Biological Chemistry
Nitric oxide, cell signaling and cell death
Toxicology
Myocardial revascularization after acute infarction
The American Journal of Cardiology
Direct EPR detection of the carbonate radical anion produced from peroxynitrite and carbon dioxide
Journal of Biological Chemistry
The diabetic disadvantage: historical outcomes measures in diabetic patients undergoing cardiac surgery-the pre-intravenous insulin era
Seminars in Thoracic and Cardiovascular Surgery
Mitochondrial free radical production and cell signaling
Molecular Aspects of Medicine
Mitochondrial free radical generation, oxidative stress, and aging
Free Radical Biology & Medicine
Myocardial hemorrhage after coronary reperfusion in pigs
The American Journal of Cardiology
Effect of off-pump coronary surgery with right ventricular assist device on organ function and inflammatory response: a randomized controlled trial
The Annals of Thoracic Surgery
Complement activation in heart diseases. Role of oxidants
Cellular Signalling
Xanthine oxidase as a source of free radical damage in myocardial ischemia
Journal of Molecular and Cellular Cardiology
Protein tyrosine nitration of the flavin subunit is associated with oxidative modification of mitochondrial complex II in the post-ischemic myocardium
Journal of Biological Chemistry
Role of 4-hydroxynonenal in modification of cytochrome c oxidase in ischemia/reperfused rat heart
Journal of Molecular and Cellular Cardiology
Depletion of cardiolipin and cytochrome c during ischemia increases hydrogen peroxide production from the electron transport chain
Free Radical Biology & Medicine
Production of reactive oxygen species by mitochondria: central role of complex III
Journal of Biological Chemistry
Mitochondrial complex II in the post-ischemic heart: oxidative injury and the role of protein S-glutathionylation
Journal of Biological Chemistry
Allopurinol pretreatment improves postoperative recovery and reduces lipid peroxidation in patients undergoing coronary artery bypass grafting
The Journal of Thoracic and Cardiovascular Surgery
Enzymic characterization and lipid composition of rat liver subcellular membranes
Biochimica et Biophysica Acta
The effects of propofol on lipid peroxidation and inflammatory response in elective coronary artery bypass grafting
Journal of Cardiothoracic and Vascular Anesthesia
The effects of propofol on neutrophil function, lipid peroxidation and inflammatory response during elective coronary artery bypass grafting in patients with impaired ventricular function
British Journal of Anaesthesia
NO synthase: structures and mechanisms
Nitric Oxide
Detection of hydroxyl radical in the mitochondria of ischemic-reperfused myocardium by trapping with salicylate
Biochemical and Biophysical Research Communications
Nitric oxide synthase activities in human myocardium
Lancet
Propofol attenuates peroxynitrite-mediated DNA damage and apoptosis in cultured astrocytes: an alternative protective mechanism
Anesthesiology
Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury
The FASEB Journal
Upregulation of Nox4 by hypertrophic stimuli promotes apoptosis and mitochondrial dysfunction in cardiac myocytes
Circulation Research
The NADPH oxidase Nox4 and aging in the heart
Aging (Albany NY)
Preconditioning the human heart during aorto-coronary bypass surgery
European Journal of Cardio-Thoracic Surgery
Peroxynitrite-dependent Tryptophan nitration
Chemical Research in Toxicology
Reduction in experimental infarct size by recombinant human superoxide dismutase: insights into the pathophysiology of reperfusion injury
Circulation
Oxygen radicals generated at reflow induce peroxidation of membrane lipids in reperfused hearts
The Journal of Clinical Investigation
Improvement of postischemic myocardial function and metabolism induced by administration of deferoxamine at the time of reflow: the role of iron in the pathogenesis of reperfusion injury
Circulation
Opening mitoKATP increases superoxide generation from complex I of the electron transport chain
American Journal of Physiology. Heart and Circulatory Physiology
Propofol enhances red cell antioxidant capacity in swine and humans
Canadian Journal of Anaesthesia
High dose propofol enhances red cell antioxidant capacity during CPB in humans
Canadian Journal of Anaesthesia
Spin trapping of oxygen and carbon-centered free radicals in ischemic canine myocardium
Free Radical Biology & Medicine
Myocardial ischemia/reperfusion injury is mediated by leukocytic toll-like receptor-2 and reduced by systemic administration of a novel anti-toll-like receptor-2 antibody
Circulation
Catalase inhibition with 3-amino-1,2,4-triazole does not abolish infarct size reduction in heat-shocked rats
Circulation
The final 10-year follow-up results from the BARI randomized trial
Journal of the American College of Cardiology
Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms
Nature
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