TRPV1/SIRT1介导膳食辣椒素抗糖尿病血管老化作用研究

Decreased level of longevity protein SIRT1 induced by hyperglycaemia has been demonstrated to play a crucial role in diabetic vascular aging. Our previous study found that rutaecarpine prevented the endothelial cells senescence induced by high glucose, which is related to promoting the expression of SIRT1 via activation of TRPV1. Recently, chili or dietary capsaicin were reported to Improve glucose homeostasis and ameliorate diabetic complications. So we hypothesized that dietary can prevent the vascular aging in diabetes.The objective of the present project is to explore the effect of dietary capsaicin on vascular aging, SIRT1 and downstream P53/P21 aging pathway in diabetes mice model. Furthermore, we will explore the involvement of TRPV1/[Ca2+]i/AMPK pathway in modulation of SIRT1 by capsaicin in cultured vascular endothelial cells and smooth muscle cells. Additionally, to explore the association of vascular aging with dietary capsaicin intake, dietary capsaicin intake will be evaluated using a food frequency questionnaire in diabetes mellitus type 2. This study maybe contribute to healthy diet guide, and provide a new target TRPV1 to find drugs or functional food for preventing vascular aging.

高糖诱导的长寿蛋白SIRT1表达降低是糖尿病血管老化的重要原因。课题组前期发现中药有效成分吴茱萸次碱可抑制高糖诱导的血管内皮衰老，其机制与激活瞬时受体电位香草酸亚型1(TRPV1)后上调SIRT1表达有关。国人日常膳食中常含有的辣椒素成分是TRPV1的天然激动剂。流行病学和动物实验研究提示，辛辣食物或膳食中添加辣椒素可能影响糖尿病并发症转归。我们推测，膳食辣椒素可影响糖尿病血管老化过程。本课题拟在糖尿病动物模型观察膳食辣椒素对血管老化的影响，并从TRPV1/SIRT1及下游衰老通路P53/P21探讨其抗衰老机制；采用高糖诱导的血管内皮和平滑肌细胞衰老模型，从TRPV1/[Ca2+]i/AMPK信号途径探讨辣椒素调节SIRT1表达的分子机制；在2型糖尿病患者开展膳食调查，探讨膳食辣椒素摄入量与血管老化的相关性。本课题将为指导健康膳食及以TRPV1为靶点开发抗血管老化的功能食品或药品提供依据。

糖尿病患者血管老化加速是导致血管并发症的重要原因，而高糖诱导的长寿蛋白SIRT1表达降低导致血管老化的关键机制。瞬时受体电位香草酸亚型1(TRPV1)是调节SIRT1的潜在靶点，而国人日常膳食中常含有的辣椒素成分是TRPV1的天然激动剂。流行病学和动物实验研究提示，辛辣食物或膳食中添加辣椒素可能影响糖尿病并发症转归。本研究已从高糖诱导的血管内皮和平滑肌细胞衰老模型、2型糖尿病大鼠模型和临床2型糖尿病患者三个水平确定辣椒素具有抑制高糖诱导的血管老化和钙化的药理学作用，并阐明其机制与激活TRPV1/[Ca2+]i /CaMKII/AMPK信号通路，上调长寿蛋白SIRT，并抑制其下游衰老通路P53/P21有关。本项目发掘了膳食性辣椒素抗血管老化的新作用，阐明干预 TRPV1 调控长寿基因 SIRT1的分子机制，为指导糖尿病患者健康膳食及以TRPV1为靶点开发抗血管老化的功能食品或药品提供了实验依据。