0273 : Role of Sirtuin 3 in cardioprotection – evolution with aging

Abstract

Mitochondrial dysfunction contributes to the pathogenesis of a wide variety of common diseases, including cardiovascular diseases. Mitochondria- triggered cell death is a major cause of cardiac injury following ischemia reperfusion (I/R). Aging is a physiological evolution of organisms and the concept that mitochondrial function declines during aging has been largely described for many years. Furthermore, aging is a major risk factor for myocardial infarction. Sirtuin 3 (SIRT3) is a member of Sirtuin family which is a NAD+ dependent deacetylase, preferentially localized into mitochondria. SIRT3 deacetylates some of the regulatory components of the mitochondrial permeability transition pore (mPTP), cyclophilin D (CypD) and complexes of the electron transport chain, both known to be involved in cardioprotection. The goal of this study was to clarify the role of SIRT3 in cardioprotection following aging, and its mechanism of action through mitochondrial functions. To do so, we used WT and Sirt3 KO mice (129S6/SvEvTac) at different ages: 2, 6 and 12 months. Mice underwent in vivo acute myocardial ischemiareperfusion at different ages. The infarct size was quantified and compared between the different ages. Total mitochondrial acetylation, and acetylation level of CypD and Complex I were quantified and in parallel we assessed mPTP sensitivity to Ca2+ using Calcium Retention Capacity and Oxidative Phosphorylation. Our results show that the absence of SIRT3 prevents the beneficial effect of cardioprotection by ischemic post-conditioning. SIRT3 KO mostly changes the acetylation status of CypD and Complex I, and also increases by almost 30% mPTP sensitivity to Ca2+. We also demonstrate that aging changes SIRT3 activity, which increases protein acetylation and decreases mPTP sensitivity to Ca2+. Globally, this study enlightens the importance of SIRT3 activity as a therapeutic target in cardioprotection.