MinireviewRole of epoxyeicosatrienoic acids in protecting the myocardium following ischemia/reperfusion injury
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.
Section snippets
Arachidonic acid, CYP epoxygenases and soluble epoxide hydrolase
Arachidonic acid (AA), a polyunsaturated fatty acid normally found esterified to cell membrane glycerophospholipids, can be released by phospholipases in response to several stimuli, such as ischemia [13]. Free AA is then available for metabolism by prostaglandin H2 synthases, lipoxygenases and cytochrome P450 monooxygenases to generate numerous metabolites, collectively termed eicosanoids [14], [15]. CYP epoxygenases metabolize AA to four regioisomeric epoxyeicosatrienoic acids (5,6-, 8,9-,
Ischemic injury and cardioprotection
Ischemic heart disease is an underlying cause of most AMIs, congestive HF, arrhythmias and sudden cardiac death. Myocardial ischemia is characterized by inadequate blood flow to the heart resulting in limited glucose, oxygen and delayed metabolic by-product removal. Ultimately, ischemic events result in cellular death and myocyte loss which is the primary pathology behind many CVDs. Myocytes are not easily replaced, although stem cell therapy shows great initial promise in overcoming this
Cardioprotective signaling pathways
There is considerable controversy regarding the role of cytochrome P450s in the heart, notably the beneficial versus the detrimental effects of arachidonic acid metabolites [31], [34], [35], [39], [40], [77], [78]. We have demonstrated that EETs play a significant role in the improved postischemic functional recovery in isolated mouse hearts overexpressing CYP2J2 [31], [34], [35], [57], [78]. Recent results suggest potential cardioprotective mechanisms and indicate that KATP channels,
Conclusion
There are numerous reasons for investigating the role of this novel endogenous pathway in myocardial function and ischemic injury. First, CYP-derived metabolites of arachidonic acid play critical roles in modulating fundamental biological processes [68], [82]. Second, environmental or genetic factors that alter P450 expression and/or function lead to changes in the production of bioactive eicosanoids [68], [82]. Such effects can influence cell and organ function in either an adverse or
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2021, Redox BiologyCitation Excerpt :reduction of atherosclerosis and hypertension [13,17–21], prevention and regression of cardiac hypertrophy, failure [22–24], and fibrosis [25]. sEH is expressed in non-vascular tissues, with its inhibition limiting ischemic damage to the heart [26–31]. brain and other organs [32,33].