Abstract
Hypoxia–reoxygenation (H/R) injury is known to cause extensive injury to cardiac myocardium promoting development of cardiac dysfunction. Despite the vast number of studies dedicated to studying H/R injury, the molecular mechanisms behind it are multiple, complex, and remain very poorly understood, which makes development of novel pharmacological agents challenging. Docosahexaenoic acid (DHA, 22:6n3) is an n - 3 polyunsaturated fatty acid obtained from dietary sources, which produces numerous effects including regulation of cell survival and death mechanisms. The beneficial effects of DHA toward the cardiovascular system are well documented but the relative role of DHA or one of its more potent metabolites is unresolved. Emerging evidence indicates that cytochrome P450 (CYP) epoxygenase metabolites of DHA, epoxydocosapentaenoic acids (EDPs), have more potent biological activity than DHA in cardiac cells. In this study we examined whether EDPs protect HL-1 cardiac cells from H/R injury. Our observations demonstrate that treatment with 19,20-EDP protected HL-1 cardiac cells from H/R damage through a mechanism(s) protecting and enhancing mitochondrial quality. EDP treatment increased the relative rates of mitobiogenesis and mitochondrial respiration in control and H/R exposed cardiac cells. The observed EDP protective response toward H/R injury involved SIRT1-dependent pathways.
Highlights
The heart is an organ with limited capacity for regeneration and repair, which makes it vulnerable to various stress factors including ischemia–reperfusion injury (IR; Kimura and Sadek, 2012)
We suggest that prolonged activation of HIF-1α in cardiac cells triggers overactivation of glycolysis leading to acidification, as observed by an increased ratio between lactate and pyruvate, where acidification acts as a toxicant triggering death of cardiomyocytes
Activating HIF-1α downregulates key mitochondrial machinery, which is detrimental to cardiomyocytes over the long-term run as metabolic activity and cellular function are strongly dependent on optimally functioning mitochondria
Summary
The heart is an organ with limited capacity for regeneration and repair, which makes it vulnerable to various stress factors including ischemia–reperfusion injury (IR; Kimura and Sadek, 2012). Existing studies consider mitochondrial dysfunction as a major factor behind the development of cardiac malfunction induced by IR (Solaini et al, 2010; Walters et al, 2012; Bayeva et al, 2013). EDPs Limit Hypoxia–Reoxygenation Injury via SIRT1 oxidative metabolism, ionic homeostasis and biogenesis results in accumulation of aberrant mitochondria and is considered the crucial factor contributing to myocardial collapse (Walters et al, 2012). These aberrant mitochondria may induce cell death exacerbating the extent of IR injury (Yamamoto and Sadoshima, 2011; Prabhakar and Semenza, 2012; Walters et al, 2012). Interest in developing strategies to protect and maintain mitochondrial homeostasis are being proposed as viable approaches to reduce the deleterious effects of IR injury (Walters et al, 2012; Bayeva et al, 2013)
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