Sirtuin 1 aggravates hypertrophic heart failure caused by pressure overload via shifting energy metabolism

Sirtuin1 (SIRT1) is involved in regulating substrate metabolism in the cardiovascular system. Metabolic homeostasis plays a critical role in hypertrophic heart failure. We hypothesize that cardiac SIRT1 can modulate substrate metabolism during pressure overload-induced heart failure. The inducible cardiomyocyte 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 pressure overload 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 pathological stress by TAC-induced pressure overload as evidenced by no significant changes in systolic contractile functions and electric properties. The targeted proteomics showed that the pressure overload triggered downregulation of the SIRT1-associated IDH2 (isocitrate dehydrogenase 2) that resulted in increased oxidative stress in mitochondria. Moreover, metabolic alterations were observed in Sirt1^f/f but not in icSirt1^-/- heart in response to TAC-induced pressure overload. Thus, SIRT1 interferes with metabolic homeostasis through mitochondrial IDH2 during pressure overload. Inhibition of SIRT1 activity benefits cardiac functions under pressure overload-related pathological conditions.