Role of the transient receptor potential vanilloid 1 (TRPV1) in diabetes mellitus-induced endothelial dysfunction: Implications for an endogenous TRPV1 agonist as a novel biomarker

在德国和世界范围内，II型糖尿病的发病率正在迅速增加。糖尿病与内皮功能障碍相关，内皮功能障碍决定微血管和大血管病理，并使糖尿病患者在接受全身麻醉时发生围手术期不良心血管事件的风险特别高。然而，目前还没有生物标志物可用于糖尿病患者高血糖诱导的内皮功能障碍的术前风险评估。此外，没有治疗选择来改善血管功能和减少糖尿病患者的疾病负担以及德国卫生保健系统的额外费用。高血压与导致器官灌注受损的内皮依赖性血管舒张受损有关。瞬时受体电位香草素1（TRPV 1）介导内皮舒张和增强器官灌注，糖尿病与内皮TRPV 1表面表达减少有关。然而，内皮TRPV 1下调的触发因素和机制完全未知。斯坦福大学的格罗斯是研究糖尿病引起的心血管功能障碍和TRPV 1细胞内受体运输的专家。他揭示了TRPV 1在大鼠心肌细胞中运输到细胞表面的新机制。此外，他发现糖尿病大鼠体内内源性TRPV 1代谢物12-羟基二十碳四烯酸（12-HETE）水平升高。在这个项目中，我的目标是将我的内皮细胞专业知识与助理教授E。恶心我的假设是，12-HETE诱导内皮TRPV 1在高血糖条件下下调和内皮TRPV 1表面表达的改善是一种治疗选择，以恢复糖尿病内皮功能。我将通过研究高血糖条件下12-HETE依赖的TRPV 1运输和内皮功能障碍来验证我的假设（AIM 1）。我将进一步验证TRPV 1作为治疗内皮功能障碍的靶点，通过用助理教授E。增强TRPV 1细胞表面表达的大体实验室（AIM 2）。我的目标是确定12-HETE作为一种新的生物标志物，用于糖尿病患者术前风险评估，评估预先存在的血管病变程度和围手术期不良心血管事件的易感性。此外，我的目标是进一步阐明内皮TRPV 1表面表达的改善作为一种有效的治疗选择，以恢复内皮功能和降低糖尿病患者的血管病理相关的发病率和死亡率。

The incidence of type II diabetes mellitus is rapidly increasing in Germany and worldwide. Diabetes mellitus is associated with endothelial dysfunction that determines micro- and macrovascular pathologies and renders diabetic patients of particular risk for the occurrence of adverse perioperative cardiovascular events when undergoing general anesthesia. However, there is currently no biomarker available that allows for preoperative risk assessment of hyperglycemia-induced endothelial dysfunction in diabetic patients. Further, there is no therapeutical option to improve vascular function and reduce disease burden of diabetic patients as well as excess costs for the German health care system.Hyperglycemia is associated with impaired endothelium-dependent vasorelaxation that results in impaired organ perfusion. The transient receptor potential vanilloid 1 (TRPV1) mediates endothelial relaxation and augmented organ perfusion and diabetes is associated with diminished endothelial TRPV1 surface expression. However the trigger and mechanism of endothelial TRPV1 downregulation are completely unknown.Asst. Prof. E. Gross at Stanford University is an expert in studying diabetes-induced cardiovascular dysfunction and TRPV1 intracellular receptor trafficking. He unraveled a novel mechanism of TRPV1 trafficking to the cell surface in rat cardiomyocytes. Furthermore, he identified elevated levels of 12-hydroxyeicosatetraenoic acid (12-HETE), an endogenous TRPV1 metabolite, in diabetic rats. In this project, I aim to join my endothelial cell expertise with the novel findings of Asst. Prof. E. Gross. My hypothesis is that 12-HETE induces endothelial TRPV1 downregulation under hyperglycemic conditions and that improvement of endothelial TRPV1 surface expression is a therapeutical option to restore endothelial function in diabetes. I will test my hypothesis by investigating 12-HETE-dependent TRPV1 trafficking and endothelial dysfunction under hyperglycemic conditions (AIM 1). I will further verify TRPV1 as a target for the therapy of endothelial dysfunction by treating diabetic rats with a peptide developed in Asst. Prof. E. Gross laboratory that enhances TRPV1 cell surface expression (AIM2). My goal is to identify 12-HETE as a novel biomarker for preoperative risk assessment of diabetic patients with regard to the degree of preexisting vascular pathology and predisposition for adverse perioperative cardiovascular events. In addition, my goal is further to unravel improvement of endothelial TRPV1 surface expression as a potent therapeutical option to restore endothelial function and reduce vascular pathology-related morbidity and mortality of diabetic patients.