血管紧张素II对糖尿病冠状动脉平滑肌细胞TRPC1-BK复合体调控及其机制研究

糖尿病已成为冠状动脉（冠脉）病变发生的一个重要危险因素，其机制可能与冠脉离子通道功能异常有关。本课题组前一个国家自然科学基金（81070157）研究发现瞬时受体电位C1通道（TRPC1通道）和大电导钙激活钾通道（BK通道）在正常冠脉平滑肌细胞上可形成功能复合体（TRPC1-BK复合体），而糖尿病时TRPC1-BK复合体表达异常，但其机制尚不清楚。本课题预实验发现血管紧张素Ⅱ（Ang-Ⅱ）可能参与TRPC1-BK复合体的调控，据此提出如下假说：糖尿病时Ang-Ⅱ通过NF-κB通路上调TRPC1通道功能，并通过MAPKs通路下调BK通道功能，导致TRPC1-BK复合体功能失衡，从而引起冠脉舒缩活动异常。本课题拟采用膜片钳、分子生物学和细胞内钙成像等实验技术，研究Ang-Ⅱ对糖尿病冠脉TRPC1-BK复合体的调控作用及其机制，研究结果可能为糖尿病患者冠脉病变治疗提供新途径。

Diabetes mellitus is an important risk factor for coronary heart disease, which may be involved by impaired function of ion channels. Transient receptor potential canonical 1 (TRPC1) and large conductance Ca2+-sensitive K channel (BK) form a complex (TRPC1-BK complex) in coronary smooth muscle cells. In the study of our previous national natural grant (81070157), we have found the BK channel current density is decreased while the TRPC1 channel expression is increased in diabetic coronary smooth muscle cells. The dysfunction of TRPC1-BK complex led to the coronary contractions. However, little is known about their mechanisms. We have found that angiotensin Ⅱ(Ang-Ⅱ) may be involved in regulating the TRPC1-BK complex in diabetic smooth muscle cells in our previous work. On the setting of our above study results, we put forward the hypothesis that Ang-Ⅱincreases the activity of TRPC1 channel by activating NF-κB, whereas decreases activity of the BK channel through MAPKs pathway in diabetic coronary arteries. To test the hypothesis, we will focus on the effects of Ang-Ⅱ on TRPC1-BK complex by applications of patch clamp technique, molecular biology technique and intracelluar calcium concentration assay in this study. Thus, TRPC1-BK complex regulated by Ang-Ⅱ may be an important contributor to the coronary pathology of diabetic individuals and, as such, is potentially attractive target for therapeutic intervention.