Abstract
While survival rates have markedly improved following cardiac ischemia-reperfusion (IR) injury, the resulting heart damage remains an important issue. Preserving mitochondrial quality and limiting NLRP3 inflammasome activation is an approach to limit IR injury, in which the mitochondrial deacetylase sirtuin 3 (SIRT3) has a role. Recent data demonstrate cytochrome P450 (CYP450)-derived epoxy metabolites, epoxydocosapentaenoic acids (EDPs), of docosahexaenoic acid (DHA), attenuate cardiac IR injury. EDPs undergo rapid removal and inactivation by enzymatic and non-enzymatic processes. The current study hypothesizes that the cardioprotective effects of the synthetic EDP surrogates AS-27, SA-26 and AA-4 against IR injury involve activation of SIRT3. Isolated hearts from wild type (WT) mice were perfused in the Langendorff mode with vehicle, AS-27, SA-26 or AA-4. Improved postischemic functional recovery, maintained cardiac ATP levels, reduced oxidative stress and attenuation of NLRP3 activation were observed in hearts perfused with the analogue SA-26. Assessment of cardiac mitochondria demonstrated SA-26 preserved SIRT3 activity and reduced acetylation of manganese superoxide dismutase (MnSOD) suggesting enhanced antioxidant capacity. Together, these data demonstrate that the cardioprotective effects of the EDP analogue SA-26 against IR injury involve preservation of mitochondrial SIRT3 activity, which attenuates a detrimental innate NLRP3 inflammasome response.
Highlights
Ischemic heart disease remains one of the primary causes of death worldwide [1,2]
We provide evidence for a novel cardioprotective mechanism of the newly synthetic epoxydocosapentaenoic acids (EDPs) surrogate SA-26
Our results suggest that the perfusion of hearts with SA-26 during the reperfusion period ameliorates ischemia reperfusion” (IR) injury by maintaining mitochondrial integrity and function
Summary
Ischemic heart disease remains one of the primary causes of death worldwide [1,2]. In patients with an ischemic event, early and successful reperfusion or restoration of blood flow to the ischemic myocardium is the most effective treatment to reduce myocardial damage and acute mortality rates [3,4]. The benefit of reperfusion is partly attenuated by paradoxical damage to cardiomyocytes that are still viable at the end of the ischemic period, a process known as “ischemia reperfusion” (IR) injury [5,6]. Evidence indicates cardiac dysfunction resulting from IR injury can be linked to mitochondrial dysfunction, excessive oxidative stress and the activation of an inflammatory response [7,8]. SIRT3 is highly expressed and localized in the mitochondria where it is essential for regulating mitochondrial homeostasis [13,14]. SIRT3 regulates mitochondrial function by deacetylating, and thereby activating, numerous mitochondrial proteins involved in energy metabolism [17], oxidative stress responses [18,19], mitochondrial dynamics [20] and the electron transport chain (ETC) [21,22]. Studies demonstrate that limiting the loss of SIRT3 following IR injury provides cardioprotective responses and highlight its importance [23,24]
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