Abstract P3138: The Regulatory Role Of Sirtuin 6 In Coronary Microvascular Dysfunction

Introduction: Coronary microvascular dysfunction (CMD) is characterized by impaired endothelial-dependent vasodilation. These impairments are seen in diabetic cardiomyopathy, ischemia with no obstructive coronary artery disease, and heart failure with preserved ejection fraction (HFpEF), but detailed mechanisms have yet to be elucidated. Sirtuin 6 (Sirt6), an important member of the Sirtuin family, has been implicated in obesity, insulin resistance, type 2 diabetes mellitus (T2DM), and cardiovascular diseases. Sirt6 protects EC from premature senescence, oxidative stress, and atherosclerosis by sustaining high eNOS levels and preserving cell replication. Sirt6 was reported to regulate endothelial dilation in atherosclerosis in Sirt6 heterozygous mice, but how Sirt6 regulates coronary microvascular function remains to be determined. Methods: Sirt6 knockout and wild-type (WT) mice were fed a diet high in fat and sugar (HFHS) for six months, and blood lipid and glucose were measured. Coronary arteries 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. Results: Our preliminary data show that Sirt6 was downregulated in diabetes. The EDD of coronary arterioles was impaired, and the mediator of coronary vasodilation switched from NO to H 2 O 2 in the Sirt6 knockout mice. Compared to the WT mice, myocardial blood flow is decreased, ejection fraction (EF) was not changed, the running distance was reduced, and E/E’ ratio was increased in Sirt6 knockout mice. The Sirt6 targeted proteins were identified. Conclusions: Sirt6 regulated coronary microvascular function, and ablation of Sirt6 caused CMD and diastolic dysfunction. Further genetic profiling will elucidate the pathways and mechanisms converging with Sirt6 to regulate microvascular function.