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

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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.