激活TRPV1促进脑血管eNOS重偶联预防卒中的机制研究

The prevention of stroke is a major task for control of cardio - and cerebrovascular disease in China. Vasomotion plays an important role in regulation of cerebral vascular function. Our preliminary studies showed that dietary capsaicin intervention could activate TRPV1,promote the vascular eNOS phosphorylation, and lower blood pressure (Cell Metab 2010). Administration of capsaicin significantly enhanced the endothelium-dependent relaxation of basilar arteries, improved the vascular remodeling and delayed the onset of stroke in stroke-prone spontaneously hypertensive rats(SHRsp)(Stroke 2011).Based on these, we plan to further reveal the mechanism of activation of TRPV1 prevention stroke. The breakthrough point of the study is that activation of TRPV1 by capsaicin effect on vasomotion and can improve the cerebral vascular eNOS uncoupling through activation of TRPV1-mediated calcium influx and changes of Cav-1 as well as up-regulation of PKCα and increase of phosphorylation GTPCH1,which results in an increase of NO production and prevention of stroke. Using multiple animal models,the study aims to explore the mechanism for the prevention of stroke through chronic dietary capsaicin at different levels.This study could help to understand the pathogenesis of vascular dysfunction in stroke. Dietary capsaicin intervention might be a new strategy for prevention of stroke.

预防卒中是我国心脑血管病的防治重点，血管节律性舒缩（Vasomotion）在脑血管功能调控和脑卒中起着重要作用。我们前期研究揭示辣椒素激活TRPV1能增加自发性高血压大鼠（SHR）血管内皮细胞钙依赖的eNOS磷酸化，降低血压（Cell Metab 2010）；辣椒素干预能改善卒中易发型高血压大鼠（SHRsp）脑血管内皮依赖的舒张功能，延缓卒中发生(Stroke 2011)。我们拟在前期工作基础上深入揭示激活TRPV1预防脑卒中的机制。本研究新的切入点是阐明辣椒素激活TRPV1介导细胞内钙信号是否影响脑血管Vasomotion，其机制是否与血管内皮Cav-1的改变，激活PKCα促使GTPCH1磷酸化，增加BH4及NO的生成，减少超氧阴离子，促进脑血管eNOS重偶联有关。本研究拟用多种动物模型，从不同层次阐明上述问题,加深对脑卒中血管功能异常发生机制的认识，为膳食辣椒素干预脑卒中提供新的策略。

预防脑卒中是我国心脑血管病防治的重点，血管节律性舒缩功能在脑血管功能和脑卒中调控中起着重要作用。本研究拟阐述激活辣椒素受体TRPV1促进脑血管eNOS重耦联在脑卒中发生中的作用和机制，为人群早期非药物干预预防脑卒中、减少心脑血管事件提供科学依据。我们通过研究发现，辣椒素干预能减少SHRsp大鼠脑组织出血灶，延缓SHRsp大鼠卒中发生；同时，辣椒素激活TRPV1能够改善脑基底动脉内皮依赖性的血管舒张功能，与基底动脉TRPV1和PKC激活有关；进一步研究发现，辣椒素干预能够在在体和离体水平抑制脑组织和内皮细胞ROS生成、促进NO生成，与辣椒素抑制Nitrotyrosine蛋白表达及改善eNOS重偶联有关，其机制与辣椒素激活TRPV1/PKCα/GTPCH1通路促进BH4的生成有关。膳食因子辣椒素可作为预防脑卒中及相关心血管疾病的一个有效干预手段。这些研究共发表SCI论文3篇，在此期间共培养博士研究生及硕士研究生各1名。期间派遣课题组成员多次参加国内外学术交流，扩大了本课题组的学术影响力，圆满的完成了计划任务。