Abstract Tu0075: The Regulatory Role of Endothelial Sirtuin 6 in Coronary Microvascular Function in Diabetes

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 gene transcriptional, stress tolerance, DNA repair, and inflammation, but how SIRT6 regulates endothelial metabolism and microvascular function in diabetes and the underlying mechanism remains poorly understood. This study will investigate how endothelial Sirt6 regulates coronary vasodilation and coronary blood flow under metabolic stress. 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. To study the endothelial Sirt6 function in diabetes, we generated non-inducible endothelial-specific Sirt6 knockout (Sirt6 f/f, tie-2 cre , Sirt6 DEC ) and inducible endothelial-specific Sirt6 knockout (Sirt6 f/f, Cdh5-cre/ERT2 , Sirt6 iDEC ). Sirt6 DEC , Sirt6 iDEC, and their littermate control mice were fed 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. Sirt6 DEC and Sirt6 iDEC mice fed on a chow diet had normal EDD and CFR. However, both mice fed on HFHS diet showed impaired coronary EDD, and switched the mediator of vasodilation from NO to H 2 O 2 , suggesting the regulatory roles of endothelial Sirt6 in coronary microvascular dysfunction under metabolic stress. The underlying mechanism and the pathways involved be further investigated.