The major goal of the project is to elucidate the molecular mechanisms underlying cardiac microvascular fatty acid transport dysfunctions and its involvement in heart failure with preserved ejection fraction (HFpEF) under diabetic conditions. Diabetes mellitus, one of the major leading chronic morbidities worldwide, is continually increasing with a high prevalence in the United States and throughout the world. Cardiovascular complications are mainly responsible for the high morbidity and mortality in people with diabetes. Type 2 diabetes (T2D) is one of key risk factors for the development of HFpEF, and the prevalence of HFpEF is rising in parallel with global surging of T2D. However, the molecular mechanisms linking diabetes to HFpEF are poorly understood, and currently there are no effective treatments available for HFpEF. Endothelium, a cell layer lining of blood vessels, is an independent organ that functions as a barrier for the nutrient shuttling. The neglected role of endothelium in controlling the metabolic homeostasis is beginning to evolve. However, the role of coronary microvascular endothelial fatty acid shuttling in diabetic heart and the underlying molecular mechanisms remain elusive. Sirtuin 6 (SIRT6), a well-recognized longevity gene, regulates genome stabilization, DNA repair, inflammation and metabolic homoeostasis. SIRT6 is a histone deacetylase that targets the acetylation of histone 3 lysine 9, an epigenetic marker for active gene transcription. Recent studies indicate that SIRT6 deficiency is associated with metabolic disease, and SIRT6 has been proposed as a potential therapeutic candidate fighting the metabolic syndrome epidemic. In parallel, emerging evidence from our group suggests that SIRT6 plays a crucial role in regulation of cardiac endothelial homeostasis. Specifically, we have recently found that SIRT6 modulates coronary microvascular endothelial fatty acid transport and cardiac lipid metabolism under the nondiabetic and diabetic conditions, which is implicated in the pathogenesis of T2D-induced HFpEF. As such we propose that an alternation of SIRT6 expression and function in coronary microvascular endothelial cells under diabetic conditions could cause cardiac microvascular endothelial fatty acid transport abnormality and cardiac metabolic disarrangement, which may cause diabetes-associated diastolic dysfunction. We will use the combination of in vitro and in vivo experiments to test this novel hypothesis. Results from proposed studies would help to understand molecular basis of endothelial FA transport, and facilitate the development of new therapeutic approaches, such as enhancing SIRT6 expression and activity, to limit diabetes-associated HFpEF, a deadly disease without any effective therapy.