SIRT6 and vascular endothelial homeostasis

该项目的主要目标是阐明心脏微血管脂肪变性的分子机制， 酸转运功能障碍及其与射血分数保留性心力衰竭（HFpEF）的关系 糖尿病状况。糖尿病是世界范围内主要的慢性疾病之一， 在美国和全世界都有很高的流行率。心血管并发症 是糖尿病患者发病率和死亡率高的主要原因。2型糖尿病（T2D）是一种 HFpEF发生的关键风险因素，HFpEF的患病率与全球 T2D的激增。然而，将糖尿病与HFpEF联系起来的分子机制知之甚少， 目前对于HFpEF没有有效的治疗方法。内皮细胞，血管的细胞层衬里， 是一个独立的器官，作为营养穿梭的屏障。被忽视的内皮作用 在控制代谢平衡方面的作用开始进化。然而，冠状动脉微血管的作用 内皮脂肪酸在糖尿病心脏中的穿梭和潜在的分子机制仍不清楚。沉默调节 6（SIRT6），一个公认的长寿基因，调节基因组稳定，DNA修复，炎症和 代谢内稳态SIRT6是一种组蛋白脱乙酰酶，靶向组蛋白3赖氨酸9的乙酰化， 活性基因转录的表观遗传标记。最近的研究表明，SIRT6缺乏与以下疾病有关： SIRT6已被提出作为对抗代谢性疾病的潜在治疗候选物。 综合症流行。与此同时，来自我们小组的新证据表明，SIRT6在以下方面起着至关重要的作用： 心脏内皮稳态的调节。具体来说，我们最近发现SIRT6调节 冠状动脉微血管内皮脂肪酸转运和心脏脂质代谢 糖尿病病症，其与T2D诱导的HFpEF的发病机制有关。因此，我们建议， 糖尿病大鼠冠状动脉微血管内皮细胞SIRT6表达及功能的变化 条件可导致心脏微血管内皮脂肪酸转运异常和心脏代谢异常 这可能导致糖尿病相关的舒张功能障碍。我们将使用的组合在 体外和体内实验来测试这一新的假设。拟议研究的结果将有助于 了解内皮细胞FA转运的分子基础，促进新的治疗药物的开发 方法，如增强SIRT6的表达和活性，以限制糖尿病相关的HFpEF，一个致命的 没有任何有效的治疗方法。

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.