Mechanisms of coronary endothelial dysfunction in diabetes

描述(由申请人提供)： 心血管并发症是糖尿病患者发病率和死亡率的重要原因。糖尿病冠脉病变已被公认为可能导致心力衰竭的危险因素。内皮细胞在维持血管张力和血运重建中起主要作用，而内皮功能障碍在糖尿病中也很常见。缝隙连接蛋白(Cxs)是细胞间通讯的重要途径，Cx40在高血压和高脂血症的发病机制中起着特别重要的作用。然而，目前尚不清楚Cx40是否与糖尿病冠状动脉血管并发症的发生有关。本应用的目的是研究Cx40在糖尿病小鼠冠状动脉内皮细胞功能障碍中的作用。这项研究的假设是，血管内皮细胞长期暴露于高血糖导致Cx40蛋白表达下调，从而增加冠状动脉血管阻力，减少心脏供血，增加糖尿病患者的死亡率。为了验证这一假说，我们提出了三个具体的目标：1)检测冠状动脉内皮细胞暴露于高血糖是否通过下调Cx40蛋白的表达来降低毛细血管密度和抑制血管功能；2)检测内皮细胞中Cx40基因的过表达是否可作为糖尿病小鼠冠状动脉内皮功能障碍的治疗方法；以及3)确定Cx40在糖尿病中的功能是否受Cx40‘S转录因子和Cx40本身的酶促0-连接糖基化调控。我的长期目标是确定糖尿病冠状动脉血管功能障碍的机制，并开发基于内皮细胞的治疗策略，以减少或防止冠状动脉血管疾病的进展。在沃尔夫冈·迪尔曼博士的指导下工作，为学习如何建立基于内皮细胞的转基因小鼠模型，在分子水平上研究Cx40在糖尿病中的功能提供了一个很好的机会。该奖项的目的是为我的独立研究项目获得支持，并促进我过渡为一名完全独立的研究员，在心血管病理生理学领域进行基础和转化性研究。 公共卫生相关性：这项研究的完成将为开发糖尿病冠状动脉血管病变的新治疗干预措施提供重要的见解。

DESCRIPTION (provided by applicant): Cardiovascular complications account for significant morbidity and mortality in diabetic patients. Diabetic coronary vascular disease has been recognized as a risk factor that may lead to heart failure. Endothelial cells play a major role in the maintenance of vascular tone and revascularization, while an endothelial dysfunction is commonly observed in diabetes. Gap junctions, formed by connexins (Cxs), provide important pathways for the cell-cell communication and Cx40 is known to be specially important in pathogenesis of hypertension and hyperlipidemia. It is, however, unclear whether Cx40 contributes to the development of coronary vascular complication in diabetes. The object of this application is to investigate the role of Cx40 in coronary endothelial dysfunction using diabetic mice. The hypothesis of this study is that chronic exposure of endothelial cells to hyperglycemia results in downregulated Cx40 protein expression, which increases coronary vascular resistance, decreases cardiac blood supply and increases mortality in diabetes. Three specific aims are proposed to test the hypothesis: 1) To examine whether exposure of coronary endothelial cells to hyperglycemia decreases capillary density and inhibits vascular function through downregulation of Cx40 protein expression; 2) To test whether overexpression of Cx40 gene in endothelial cells serves as a therapeutic approach for coronary endothelial dysfunction in diabetic mice; and 3) To determine whether Cx40 function in diabetes is controlled by enzymatic 0-linked glycosylation of Cx40's transcription factors and Cx40 itself. My long-term goal is to identify the mechanisms for diabetic coronary vascular dysfunction and to develop endothelial cell-based therapeutic strategies to reduce or prevent the progression of coronary vascular disease. To work under a mentorship of Dr. Wolfgang Dillmann provides a great opportunity to learn how to generate endothelial cell-based transgenic mouse model to investigate Cx40 function at the molecular level in diabetes. The purpose of this award is to obtain support for my independent research project and to facilitate my transition to become a fully independent investigator conducting basic and translational research in the field of cardiovascular pathophysiology. PUBLIC HEALTH RELEVANCE: Completion of this study will provide important insights into developing new therapeutic interventions for coronary vascular decease in diabetes.