Abstract 4364228: The Role of Sirtuin 6 in the Coronary Microvascular Dysfunction in Diabetes and Aging

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; however, the mechanisms by which SIRT6 regulates coronary microvascular function remain poorly understood. This study will investigate how Sirt6 regulates coronary vasodilation and coronary blood flow in physiological and pathological conditions (diabetes and aging). Global Sirt6 knockout mice are perinatally lethal because of hypoglycemia, which limits to explore the roles of Sirt6 in vivo. We generated inducible global Sirt6 knockout mice (Sirt6 f/f mice,CAG-cre , Sirt6 iD ), and the mice were viable after tamoxifen induction at 6 weeks. The Sirt6 iD 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 measured 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 to have impaired coronary vasodilation, with Sirt6 activator MDL-800 and overexpressed Sirt6. Moreover, we included 24-month-old mice. Our preliminary data showed that Sirt6 is downregulated in diabetes, a deficiency of Sirt6 impaired coronary EDD, switched the mediator of vasodilation from NO to H 2 O 2 when mice were fed a chow diet, and impaired coronary flow reserve (CFR). The phenotype was more severe when the mice were fed with an HFHS diet, 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. Moreover, the aging mice showed impaired coronary vasodilation and CFR. The underlying mechanism and the pathways involved will be further elucidated.