Role of epoxyeicosatrienoic acids in protecting the myocardium following ischemia/reperfusion injury

Abstract

Cardiomyocyte injury following ischemia–reperfusion can lead to cell death and result in cardiac dysfunction. A wide range of cardioprotective factors have been studied to date, but only recently has the cardioprotective role of fatty acids, specifically arachidonic acid (AA), been investigated. This fatty acid can be found in the membranes of cells in an inactive state and can be released by phospholipases in response to several stimuli, such as ischemia. The metabolism of AA involves the cycloxygenase (COX) and lipoxygenase (LOX) pathways, as well as the less well characterized cytochrome P450 (CYP) monooxygenase pathway. Current research suggests important differences with respect to the cardiovascular actions of specific CYP mediated arachidonic acid metabolites. For example, CYP mediated hydroxylation of AA produces 20-hydroxyeicosatetraenoic acid (20-HETE) which has detrimental effects in the heart during ischemia, pro-inflammatory effects during reperfusion and potent vasoconstrictor effects in the coronary circulation. Conversely, epoxidation of AA by CYP enzymes generates 5,6-, 8,9-, 11,12- and 14,15-epoxyeicosatrienoic acids (EETs) that have been shown to reduce ischemia–reperfusion injury, have potent anti-inflammatory effects within the vasculature, and are potent vasodilators in the coronary circulation. This review aims to provide an overview of current data on the role of these CYP pathways in the heart with an emphasis on their involvement as mediators of ischemia–reperfusion injury. A better understanding of these relationships will facilitate identification of novel targets for the prevention and/or treatment of ischemic heart disease, a major worldwide public health problem.

Introduction

Heart disease and stroke are major causes of illness, disability and death in Western societies, and impose a great burden to national health care systems [1], [2], [3], [4], [5], [6]. For example, cardiovascular disease (CVD) accounted for the death of approximately 76,500 Canadians in 2002 [2], [4] and over 910,000 individuals in the US [6]. As the population ages and co-morbidities, such as obesity and diabetes become more prevalent, both the human cost and economic burden of CVD will likely increase. Acute myocardial infarction (AMI) continues to be a leading cause of death worldwide [7], [8]. Myocardial infarction occurs when ischemia exceeds a critical threshold and overwhelms cellular repair mechanisms that are designed to maintain normal operating function and homeostasis. Ischemia at this critical threshold level results in irreversible myocardial cell damage or death. Such injury contributes to the pathogenesis of heart failure (HF), AMI and sudden death [9]. Advances in early reperfusion therapy, such as thromobolytic drugs, coronary angioplasty or bypass graft surgery, have reduced morbidity, HF and infarct-associated ventricular arrhythmias. Preconditioning (PC) is another powerful cardioprotective strategy that renders the heart resistant to injury [10]. Brief, non-detrimental episodes of ischemia or pharmacological mimetics given prior to a prolonged ischemic event can initiate signaling events that protect the myocardium [10]. Unfortunately, both early reperfusion therapy and cardioprotective drugs given prior to ischemia have limited clinical utility as patients typically present after the onset of ischemia and/or are unable to reach medical facilities [11], [12]. In light of the increasing incidence and prevalence of HF after AMI [1], [3], [4], there is a profound need for a better understanding of the underlying pathophysiology and a need for development of strategies to protect the myocardium from ischemic-reperfusion injury. Thus, novel therapeutic strategies are required in order to prevent the adverse consequences and impact of CVD.