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) 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 but not icSirt1 mice. The cardiac contractile dysfunctions caused by TAC-induced pressure overload occurred in Sirt1 but not in icSirt1 mice. Intriguingly, Sirt1 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 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.