The Role of Sirtuin 6 in Regulating the Coronary Microvascular Function

Coronary microcirculation is essential to maintaining normal cardiac function. When the cardiac metabolic demand increases (e.g., exercise or stress), coronary blood flow increases accordingly to meet the needs. However, when coronary vasodilation is impaired or coronary microvascular dysfunctions, the balance of supply and demand breaks. Deficiency of myocardial blood flow causes myocardial ischemia. Coronary microvascular dysfunction (CMD) is associated with diabetic cardiomyopathy and heart failure with preserved ejection fraction (HFpEF), but detailed mechanisms have yet to be elucidated. Nuclear Sirtuin 6 (SIRT6) plays essential roles in cardiovascular homeostasis, but how SIRT6 regulates coronary microvascular function, and the underlying mechanism remains poorly understood. This study will investigate how Sirt6 regulates coronary vasodilation and coronary blood flow in the physiological and pathological condition (diabetes). Global Sirt6 knockout mice are perinatally lethal because of hypoglycemia, suggesting the essential role of SIRT6 in metabolism. In our preliminary studies, Sirt6 is downregulated in diabetes. We generated inducible global Sirt6 knockout mice (Sirt6 f/f mice, CAG-cre , Sirt6 i D ), and the mice were viable after tamoxifen induction. The Sirt6 i D mice and their littermate controls were fed with a chow or a high-fat, high-sugar (HFHS) diet. We isolated coronary arterioles to measure endothelial-dependent dilation (EDD) by myography (DMT) and measure myocardial blood flow (MBF) and coronary flow reserve (CFR), an index clinically used to diagnose CMD. To study the role of Sirt6 in coronary microcirculation in diabetes, we treated the diabetic mice (Tallyho), which were reported with impaired coronary vasodilation, with Sirt 6 activator MDL-800. Our preliminary data showed that deficiency of Sirt6 impaired coronary EDD, switched the mediator of vasodilation from NO to H 2 O 2 when mice were fed with a chow diet, and impaired CFR. When mice were fed with an HFHS diet, deficiency of Sirt6 impaired the coronary vasodilation, and CFR was significantly decreased, accompanied by severe hyperglycemia and insulin resistance. Interestingly, the Sirt6 activator ameliorated coronary EDD and CFR in diabetic mice, suggesting the therapeutic roles of Sirt6 in CMD in diabetes. The underlying mechanism and the pathways involved will be further elucidated. AHA and NIH This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.