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

12(S)-HpETE/TRPV1 相互作用介导高血糖诱导的内皮功能障碍：糖尿病血管病理早期诊断和治疗的新方法

• 批准号: 390645560
• 负责人: Professorin Dr. Nana-Maria Wagner
• 金额: --
• 依托单位: Klinik und Poliklinik für Anästhesiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/390645560?language=en
• 关键词: 12; HpETE; TRPV1; interaction; mediates

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.

9% 的德国人口患有糖尿病。糖尿病会导致血管疾病，糖尿病患者在接受手术和麻醉时发生不良心血管并发症的风险增加。然而，目前还没有生物标志物能够通过反映先前存在的血管病理程度来对糖尿病患者进行术前风险分层。内皮功能障碍先于糖尿病引起的血管病理，并且本质上促成了糖尿病引起的血管病理。其特征是与内皮细胞线粒体功能障碍和线粒体钙超载相关的内皮依赖性血管舒张减少。在斯坦福大学医学院进行研究期间，我发现糖尿病大鼠中花生四烯酸代谢物 12(S)-氢过氧二十碳四烯酸 (12(S)-HpETE) 的血浆浓度升高。 12(S)-HpETE 是瞬时受体电位香草酸 1 (TRPV1) 的内源性激活剂，TRPV1 是一种离子通道，主要门控钙 I，该离子通道位于先前未识别的位置，即内皮细胞线粒体。在我的初步研究中，与辣椒素或高水平葡萄糖 (25mM) 激活 TRPV1 相比，用 12(S)-HpETE 激活 TRPV1 会诱导内皮细胞中的线粒体钙流入和线粒体功能障碍。 12(S)-HpETE 的这些作用在存在对应于 TRPV1 上推定的 12(S)-HpETE/TRPV1 相互作用位点的肽诱饵 (V1-cal) 的情况下被消除。我的假设是，内皮细胞响应高葡萄糖浓度而产生的 12(S)-HpETE 浓度增加，通过诱导 TRPV1 介导的线粒体功能障碍，介导糖尿病的内皮功能障碍。基于这一机制，我的目标是确定 12(S)-HpETE 可以作为生物标志物来识别血糖控制不佳和早期血管疾病的患者。通过识别 12(S)-HpETE/TRPV1 相互作用位点，我的目标是在体外产生一种能够抵抗高葡萄糖浓度有害影响的内皮细胞系，并在小鼠模型中使用 V1-cal 逆转糖尿病诱导的内皮功能障碍。体内。最终，对于该提案，我的长期目标是建立一种新的诊断和治疗策略，以降低糖尿病患者的围手术期风险和合并症的发生率。