12(S)-HpETE/TRPV1 interaction mediates hyperglycemia-induced endothelial dysfunction: Novel approaches to early diagnosis and therapy of vascular pathology in diabetes mellitus

• Applicant: Professorin Dr. Nana-Maria Wagner
• Subject Area: Anaesthesiology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 390645560

Diabetes mellitus affects 9% of the German population. Diabetes mellitus leads to vascular disease and patients with diabetes mellitus have an increased risk to suffer from adverse cardiovascular complications when undergoing surgery and anesthesia. However, there is currently no biomarker that allows for preoperative risk stratification of diabetic patients by reflecting the degree of preexisting vascular pathology. Endothelial dysfunction precedes and essentially contributes to diabetes mellitus-induced vascular pathology. It is characterized by reduced endothelium-dependent vasodilation associated with mitochondrial dysfunction and mitochondrial calcium overload in endothelial cells. During my research stay at Stanford University Medical School, I found increased plasma concentrations of the arachidonic acid metabolite 12(S)-hydroperoxyeicosatetraenoic acid (12(S)-HpETE) in diabetic rats. 12(S)-HpETE is an endogenous activator of the transient receptor potential vanilloid 1 (TRPV1), an ion channel primarily gating calcium I identified at a previously unrecognized localization, namely at endothelial cell mitochondria. In my preliminary studies, activation of TRPV1 with 12(S)-HpETE induced mitochondrial calcium influx and mitochondrial dysfunction in endothelial cells comparably to TRPV1 activation by capsaicin or high levels of glucose (25mM). These effects of 12(S)-HpETE were abolished in the presence of a peptide decoy (V1-cal) corresponding to the putative 12(S)-HpETE/TRPV1 interaction site at TRPV1. My hypothesis is, that increased 12(S)-HpETE concentrations generated in endothelial cells in response to high glucose concentrations mediate endothelial dysfunction in diabetes mellitus by inducing TRPV1-mediated mitochondrial dysfunction. Based on this mechanism, I aim to identify 12(S)-HpETE can serve as a biomarker to identify patients with poor glucose control and early stage vascular disease. By identifying the 12(S)-HpETE/TRPV1 interaction site, I aim to generate an endothelial cell line resistant to the detrimental effects of high glucose concentrations in vitro and reverse diabetes mellitus-induced endothelial dysfunction using V1-cal in a mouse model in vivo. Ultimately, for this proposal my long-term goal is to establish a new diagnostic and therapeutic strategy to lower perioperative risk and the incidence of co-morbidities in patients with diabetes mellitus.

• DFG Programme: Research Grants