The cellular and molecular origin of reactive oxygen species generation during myocardial ischemia and reperfusion

https://doi.org/10.1016/j.pharmthera.2011.11.004Get rights and content

Abstract

Myocardial ischemia-reperfusion injury is an important cause of impaired heart function in the early postoperative period subsequent to cardiac surgery. Reactive oxygen species (ROS) generation increases during both ischemia and reperfusion and it plays a central role in the pathophysiology of intraoperative myocardial injury. Unfortunately, the cellular source of these ROS during ischemia and reperfusion is often poorly defined. Similarly, individual ROS members tend to be grouped together as free radicals with a uniform reactivity towards biomolecules and with deleterious effects collectively ascribed under the vague umbrella of oxidative stress. This review aims to clarify the identity, origin, and progression of ROS during myocardial ischemia and reperfusion. Additionally, this review aims to describe the biochemical reactions and cellular processes that are initiated by specific ROS that work in concert to ultimately yield the clinical manifestations of myocardial ischemia-reperfusion. Lastly, this review provides an overview of several key cardioprotective strategies that target myocardial ischemia-reperfusion injury from the perspective of ROS generation. This overview is illustrated with example clinical studies that have attempted to translate these strategies to reduce the severity of ischemia-reperfusion injury during coronary artery bypass grafting surgery.

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)

  • B.H. Bielski et al.

    A study of the reactivity of HO2/O2- with unsaturated fatty acids

    Journal of Biological Chemistry

    (1983)
  • G.A. Blaise et al.

    Nitric oxide, cell signaling and cell death

    Toxicology

    (2005)
  • H. Bolooki

    Myocardial revascularization after acute infarction

    The American Journal of Cardiology

    (1975)
  • M.G. Bonini et al.

    Direct EPR detection of the carbonate radical anion produced from peroxynitrite and carbon dioxide

    Journal of Biological Chemistry

    (1999)
  • J.R. Brown et al.

    The diabetic disadvantage: historical outcomes measures in diabetic patients undergoing cardiac surgery-the pre-intravenous insulin era

    Seminars in Thoracic and Cardiovascular Surgery

    (2006)
  • E. Cadenas

    Mitochondrial free radical production and cell signaling

    Molecular Aspects of Medicine

    (2004)
  • E. Cadenas et al.

    Mitochondrial free radical generation, oxidative stress, and aging

    Free Radical Biology & Medicine

    (2000)
  • R.J. Capone et al.

    Myocardial hemorrhage after coronary reperfusion in pigs

    The American Journal of Cardiology

    (1978)
  • M. Caputo et al.

    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

    (2002)
  • T. Chakraborti et al.

    Complement activation in heart diseases. Role of oxidants

    Cellular Signalling

    (2000)
  • D.E. Chambers et al.

    Xanthine oxidase as a source of free radical damage in myocardial ischemia

    Journal of Molecular and Cellular Cardiology

    (1985)
  • C.L. Chen et al.

    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

    (2008)
  • J. Chen et al.

    Role of 4-hydroxynonenal in modification of cytochrome c oxidase in ischemia/reperfused rat heart

    Journal of Molecular and Cellular Cardiology

    (2001)
  • Q. Chen et al.

    Depletion of cardiolipin and cytochrome c during ischemia increases hydrogen peroxide production from the electron transport chain

    Free Radical Biology & Medicine

    (2006)
  • Q. Chen et al.

    Production of reactive oxygen species by mitochondria: central role of complex III

    Journal of Biological Chemistry

    (2003)
  • Y.R. Chen et al.

    Mitochondrial complex II in the post-ischemic heart: oxidative injury and the role of protein S-glutathionylation

    Journal of Biological Chemistry

    (2007)
  • J.G. Coghlan et al.

    Allopurinol pretreatment improves postoperative recovery and reduces lipid peroxidation in patients undergoing coronary artery bypass grafting

    The Journal of Thoracic and Cardiovascular Surgery

    (1994)
  • A. Colbeau et al.

    Enzymic characterization and lipid composition of rat liver subcellular membranes

    Biochimica et Biophysica Acta

    (1971)
  • T.B. Corcoran et al.

    The effects of propofol on lipid peroxidation and inflammatory response in elective coronary artery bypass grafting

    Journal of Cardiothoracic and Vascular Anesthesia

    (2004)
  • T.B. Corcoran et al.

    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

    (2006)
  • S. Daff

    NO synthase: structures and mechanisms

    Nitric Oxide

    (2010)
  • D.K. Das et al.

    Detection of hydroxyl radical in the mitochondria of ischemic-reperfused myocardium by trapping with salicylate

    Biochemical and Biophysical Research Communications

    (1989)
  • A.J. de Belder et al.

    Nitric oxide synthase activities in human myocardium

    Lancet

    (1993)
  • R. Acquaviva et al.

    Propofol attenuates peroxynitrite-mediated DNA damage and apoptosis in cultured astrocytes: an alternative protective mechanism

    Anesthesiology

    (2004)
  • V.J. Adlam et al.

    Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury

    The FASEB Journal

    (2005)
  • T. Ago et al.

    Upregulation of Nox4 by hypertrophic stimuli promotes apoptosis and mitochondrial dysfunction in cardiac myocytes

    Circulation Research

    (2010)
  • T. Ago et al.

    The NADPH oxidase Nox4 and aging in the heart

    Aging (Albany NY)

    (2010)
  • A.M. Alkhulaifi et al.

    Preconditioning the human heart during aorto-coronary bypass surgery

    European Journal of Cardio-Thoracic Surgery

    (1994)
  • B. Alvarez et al.

    Peroxynitrite-dependent Tryptophan nitration

    Chemical Research in Toxicology

    (1996)
  • G. Ambrosio et al.

    Reduction in experimental infarct size by recombinant human superoxide dismutase: insights into the pathophysiology of reperfusion injury

    Circulation

    (1986)
  • G. Ambrosio et al.

    Oxygen radicals generated at reflow induce peroxidation of membrane lipids in reperfused hearts

    The Journal of Clinical Investigation

    (1991)
  • G. Ambrosio et al.

    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

    (1987)
  • A. Andrukhiv et al.

    Opening mitoKATP increases superoxide generation from complex I of the electron transport chain

    American Journal of Physiology. Heart and Circulatory Physiology

    (2006)
  • D.M. Ansley et al.

    Propofol enhances red cell antioxidant capacity in swine and humans

    Canadian Journal of Anaesthesia

    (1998)
  • D.M. Ansley et al.

    High dose propofol enhances red cell antioxidant capacity during CPB in humans

    Canadian Journal of Anaesthesia

    (1999)
  • C.M. Arroyo et al.

    Spin trapping of oxygen and carbon-centered free radicals in ischemic canine myocardium

    Free Radical Biology & Medicine

    (1987)
  • F. Arslan et al.

    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

    (2010)
  • Y. Auyeung et al.

    Catalase inhibition with 3-amino-1,2,4-triazole does not abolish infarct size reduction in heat-shocked rats

    Circulation

    (1995)
  • BARI-Investigators

    The final 10-year follow-up results from the BARI randomized trial

    Journal of the American College of Cardiology

    (2007)
  • L.A. Barouch et al.

    Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms

    Nature

    (2002)
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