Abstract
Introduction: Sirtuin1 (SIRT1) serves as a deacetylase to regulate cardiac substrate metabolism during physiological and pathological conditions. The alteration in metabolic homeostasis plays a critical role in hypertrophic heart failure. Hypothesis: Cardiomyocyte SIRT1 modulates substrate metabolism to regulate cardiac remodeling during pressure overload-induced heart failure. Methods: The inducible cardiomyocyte specific Sirt1 knockout (icSirt1 -/- ) and its wild type littermates (Sirt1 f/f ) C57BL/6J mice were subjected to transverse aortic constriction (TAC) surgery to induce pressure overload. The cardiac functions were evaluated with echocardiography and electrocardiography measurements. Results: The pressure overload by TAC induces upregulation of cardiac SIRT1 in Sirt1 f/f but not icSirt1 -/- mice. The cardiac contractile dysfunctions caused by TAC-induced pressure overload occurred in Sirt1 f/f but not in icSirt1 -/- mice. Intriguingly, Sirt1 f/f heart showed a drastic reduction in systolic contractility and electric signals during post-TAC surgery, whereas icSirt1 -/- heart demonstrated significant resistance to the pathological stress by TAC-induced pressure overload as evidenced by no significant changes in systolic contractile functions and electric properties. The Seahorse data revealed that TAC-induced pressure overload causes a decrease in basal respiration and ATP generation, as well as reduced OXPHOS (oxidative phosphorylation) integrity of mitochondria in Sirt1 f/f but not in icSirt1 -/- cardiomyocytes. The targeted proteomics showed that the pressure overload trigged downregulation of the SIRT1-associated IDH2 (isocitrate dehydrogenase 2) that result in an increased oxidative stress in mitochondria. Moreover, a significant alteration in substrate metabolism was observed in Sirt1 f/f but not in icSirt1 -/- heart in response to TAC-induced pressure overload stress. Conclusions: SIRT1 interferes metabolic homeostasis through regulating mitochondrial IDH2 during pressure overload. Inhibition of SIRT1 activity benefits cardiac functions under pressure overload-related pathological conditions. SIRT1 antagonism could be a pharmacological approach for hypertrophic heart failure patients.
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