The regulatory role of Sirtuin 6 in coronary endothelial dysfunction in HFpEF

Sirtuin 6 (Sirt6) has been implicated in obesity, insulin resistance, type 2 diabetes mellitus, and cardiovascular diseases. Sirt6 protects EC from premature senescence, oxidative stress, and atherosclerosis by sustaining high eNOS levels and preserving cell replication. A recent publication showed that overexpressed Sirt 6 in EC mitigated heart failure with preserved ejection fraction (HFpEF) in diabetes. We hypothesize Sirt 6 regulates coronary microvascular dysfunction (CMD) in HFpEF associated with diabetic cardiomyopathy. CMD is characterized by impaired endothelial-dependent vasodilation, but detailed mechanisms have yet to be elucidated. How Sirt6 regulates coronary microvascular function remains to be determined. Inducible Sirt6 endothelial-specific knockout and wild-type (WT) mice were fed a chow or high fat and sugar (HFHS) diet. Coronary arterioles were isolated, and endothelial-dependent vasodilation (EDD) was assessed using myography (DMT). Echocardiography and treadmill exercise exertion tests were performed to evaluate cardiac function. Myocardial blood flow (MBF) was measured by doppler. Cardiac fibrosis was detected using trichrome staining, and molecular pathways were elucidated via gene and protein analysis. Our preliminary data show that the EDD of coronary arterioles of Sirt6 endothelial-specific knockout treated with HFHS was impaired, and the mediator of coronary vasodilation switched from NO to H2O2 in the Sirt6 knockout mice. Compared to the WT mice, myocardial blood flow and cardiac function were changed in Sirt6 knockout mice. Our data suggest that Sirt6 regulated coronary microvascular function through endothelial cells, and ablation of Sirt6 in endothelial cells caused CMD and diastolic dysfunction, eventually HFpEF. Further genetic profiling will elucidate the pathways and mechanisms converging with Sirt6 to regulate microvascular function in HFpEF. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.