Abstract
Bacterial LPS is an environmental toxin capable of promoting various cardiac complications. Current evidence suggests that LPS-induced myocardial dysfunction emerges as a consequence of compromised quality of cardiac mitochondria. Docosahexaenoic acid (DHA, 22:6n3) is an n-3 polyunsaturated fatty acid (PUFA), which produces a broad spectrum of intrinsic physiological effects including regulation of cell survival and death mechanisms. Although, numerous studies revealed fundamentally beneficial effects of DHA on cardiovascular system, it remains unknown whether these effects were produced by DHA or one of its possibly more potent metabolites. Emerging evidence indicates that cytochrome P450 (CYP) epoxygenase metabolites of DHA, epoxydocosapentaenoic acids (EDPs), produce more potent biological activity compared to its precursor DHA. In this study, we investigated whether DHA and its metabolite 19,20-EDP could protect HL-1 cardiac cells against LPS-induced cytotoxicity. We provide evidence that exogenously added or DHA-derived EDPs promote mitochondrial biogenesis and function in HL-1 cardiac cells. Our results illustrate the CYP epoxygenase metabolite of DHA, 19,20-EDP, confers extensive protection to HL-1 cardiac cells against LPS-induced cytotoxicity via activation of SIRT1.
Highlights
Cardiovascular disease remains a leading cause of morbidity and mortality worldwide
As SIRT1 positively regulates mitochondrial quality, we examined whether 19,20-epoxydocosapentaenoic acids (EDPs) could modulate SIRT1 activity and affect NAD/NADH ratios in HL-1 cells exposed to LPS
cytochrome P450 (CYP) epoxygenases catalyze the enzymatic transformation of polyunsaturated fatty acids (PUFAs) into biologically active epoxylipid mediators, such as omega-6 epoxides of arachidonic acid (AA), EETs and omega-3 epoxides of docosahexaenoic acid (DHA), EDPs.[9]
Summary
Cardiovascular disease remains a leading cause of morbidity and mortality worldwide. many differing factors contribute to the etiology, recent data suggest the bacterial endotoxin, lipopolysaccharide (LPS) has a significant role in causing numerous cardiovascular complications.[1]. Current models postulate LPS-induced cardiotoxicity occurs as a direct result of inflammatory injury of mitochondria promoting cell death.[4,5] the precise cellular and molecular mechanisms underlying these events remain poorly understood. Considering, LPS may trigger cardiac dysfunction by causing mitochondrial injury; the current study builds upon our previous data allowing to hypothesize that EDPs protect cells by protecting mitochondrial homeostasis. Recent evidence demonstrates a crucial role for SIRT1 and SIRT3 in promoting mitochondrial biogenesis, function and mitohormesis.[12,13] As well, activation of SIRT1 has been shown to confer protection against various pathophysiological conditions.[14,15] We investigate whether EDP-associated enhancement and preservation of cardiac mitochondrial quality requires activation of SIRT1 signaling to reduce LPS-induced cytotoxicity
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