Abstract 12199: Sirtuin1 Mediates Pressure Overload-Induced Cardiac Pathological Hypertrophy Through Regulating Mitochondrial Dynamics

Abstract

Introduction: Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent histone deacetylase. We revealed that the pressure-overload-induced SIRT1 can exacerbate cardiac systolic dysfunction. But the mechanisms by which SIRT1 undermines cardiac function under pathological conditions remain unclear. Hypothesis: SIRT1 induced by pathological hypotrophy disturbs mitochondrial dynamics homeostasis resulting in an exacerbated cardiac dysfunction. Methods: Wild-type littermates SIRT1 f/f (3-5 months) and inducible cardiomyocyte-specific SIRT1 knockout (icSIRT1 -/- ) (3-5 months) C57BL/6J mice were subjected to transverse aortic constriction (TAC) surgery for six weeks. Echocardiography assessed cardiac functions and CODA tail-cuff system measured blood pressure. The mitochondrial dynamics were examined by immunoblotting and transmission electron microscopy (TEM). Results: The echocardiography showed that there were significant reductions in ejection fraction (EF) and fractional shortening (FS) of the SIRT1 f/f mice after 6-weeks of TAC-induced pressure overload. The diastolic and systolic blood pressure were increased in SIRT1 f/f mice during TAC surgery. Intriguingly, icSIRT1 -/- versus SIRT1 f/f demonstrated significant resistance to pathological hypertrophy caused by TAC-induced pressure overload as determined with echocardiography and blood pressure measurements. The immunoblotting revealed that the six weeks of TAC surgery caused significantly higher levels of the mitochondrial fusion protein, mitofusin 2 (MFN2), in SIRT1 f/f versus icSIRT1 -/- hearts. In addition, TEM data showed more elongated mitochondria in SIRT1 f/f versus icSIRT1 -/- hearts, indicating a critical role of SIRT1 in maintaining mitochondrial dynamic homeostasis under pathological stress conditions. Metabolomics and proteomics showed that SIRT1 regulates carnitine palmitoyltransferase-1 and long-chain acyl CoA dehydrogenase to modulate fatty acid metabolism in response to TAC-induced stress. Conclusions: Cardiomyocyte SIRT1 plays a key role in cardiac mitochondrial dynamics during pathological stress conditions. Inhibition of SIRT1 activity could be a good strategy to ameliorate pressure overload-induced hypertrophy.