0433 : Sirtuin 3: does cardiomyocyte care?

Cardioprotection consists in reducing reperfusion injury, by acting before ischemia (preconditioning) or before reperfusion (postconditioning IPC). Sirtuins have been widely studied, and particularly mitochondrial Sirtuin 3 (SIRT3). It has been demonstrated that in the absence of this deacetylase, IPC failed at reducing infarct size (IS) in young mice. We suggested that the absence of SIRT3 lead to hyperacetylation of cyclophilin D (CypD), the major regulator of the mitochondrial permeability transition pore (mPTP), causing a mPTP hypersensitization to Ca2+ overload. To go further, we tested the effect of the absence of SIRT3 on IS in older mice, and sought to clarify the role of SIRT3 in mitochondrial functions. To do so, we used WT and SIRT3 KO mice (129S6/SvEvTac) at 2, 12 and 18 months. Mitochondrial functions were determined by calcium retention capacity (CRC) and oxidative phosphorylation (OxPhos). Mice underwent in vivo acute myocardial ischemia reperfusion, and IS was quantified.Protein expression and acetylation levels were assessed by western blot. We then tested the effect of PC by NMN, a NAD+ precursor and deacetylation enhancer via SIRT3 activation. No evidence was found on SIRT3 implication in cardioprotection in older mice. The major difference found between WT and SIRT3 KO mice was the acetylation level of mitochondrial proteins. Indeed, no significant difference was found between WT and SIRT3 KO mice over 2 m. IS increased with age for both, and IPC failed at reducing infarct size at 18 m. No difference was reported in mitochondrial functions or in protein expression after 2 m. Even a supplementation in NAD+ via NMN injection failed at reducing IS while reducing acetylation levels. Given the absence of effect of SIRT3 knock out on IS, cardioprotection and mitochondrial functions, the absence of effect of acetylation modification using NMN, we wonder what is the relevance of acetylation/de-acetylation status in cardioprotection in old mice? The author hereby declares no conflict of interest