TRPP2-STIM1复合物在冠脉平滑肌收缩和心肌缺血中的作用研究

Coronary artery spasm (CAS) is the main reason inducing myocardial ischemic in coronary atherosclerosis. But the underlying mechanisms are still poorly understood. Store-orperated Ca2+_ entry (SOCE) is one of important pathways to mediate Ca2+ influx, which can induce vascular smooth muscle cells (VSMCs) contraction. Even we have found that TRPP2 associates with STIM1 to form a signal complex involving SOCE. However, to date it is unknown whether TRPP2-STIM1 complex participates in CAS. Based on priveous findings, we speculate that TRPP2 may interact with STIM1 to regulate SOCE activity, which then modulates intracellular Ca2+ and induces CAS. The interaction between TRPP2 and STIM1 may be increased in VSMCs of the coronary having atherosclerosis to enhance CAS. Therefore，in the present study we prepare to demonstrate: (1) TRPP2-STIM1 interaction in VSMCs from the coronary artery; (2) change of agonist-induced coronary artery contraction after suppressing TRPP2 or STIM1 expression via specific siRNA; (3) change of the expression and interaction of TRPP2 and STIM1 in VSMCs from the coronary artery in coronary atherosclerosis rat; (4) change of the heart ischemia after suppressing TRPP2 or STIM1 expression via specific shRNA trasfected by virus in coronary atherosclerosis rat. The present study may be valuable for further understanding contraction mechanism of coronary VSMCs, and providing the theoretical foundation in the clinical treatment of coronary heart disease.

冠脉粥样硬化并发痉挛引起严重心肌缺血的发病机制仍不明确。SOCE是细胞外Ca2+内流的一种重要方式且可引起血管平滑肌细胞收缩。虽然我们发现内质网蛋白TRPP2和 STIM1存在相互作用，并都参与SOCE。但TRPP2和STIM1是否参与冠脉痉挛仍未阐明。我们推测：TRPP2通过与STIM1的相互作用调节SOCE活性，改变细胞内Ca2+浓度，引起冠脉痉挛；粥样硬化冠脉平滑肌TRPP2-STIM1相互作用增强，痉挛加重。因此计划：1检测冠脉平滑肌TRPP2和STIM1的相互作用；2采用siRNA抑制TRPP2或STIM1表达后检测冠脉血管收缩张力变化；3建立大鼠冠脉粥样硬化模型，检测TRPP2及STIM1在粥样硬化冠脉平滑肌的表达及结合方式改变；4慢病毒导入shRNA抑制冠脉粥样硬化大鼠TRPP2或STIM1表达,检测心肌缺血程度的变化。试图阐明冠脉平滑肌收缩机制，为冠心病的治疗提供理论依据。

心脏缺血性疾病的高危因素包括高盐和高同型半胱氨酸血症，冠脉血流量下降，冠脉血管张力受损是心脏缺血性疾病关键发病机制。内皮素、血栓环素、血管紧张素通过作用于G蛋白联受体引起冠脉收缩力增加。G蛋白偶联受体下游通路IP3受体-SOCE途经关键性调节血管平滑肌细胞收缩，此线索在疾病状态下冠脉张力调节尚不明确。本研究通过给大鼠高盐及高同型半胱氨酸饮食造成心脏缺血性疾病模型，观察大鼠冠脉张力变化和结构变化并探讨SOCE相关分子机制。结果发现：高盐高血压组U46619和ET-1引起的冠状动脉收缩明显低于对照组。进一步的分子机制为高盐诱导的高血压大鼠冠状动脉SOCE介导的收缩降低且SOCE蛋白表达下降。在病理观察中发现了冠状动脉纤维化表现。高同型半胱氨酸饮食亦引起冠状动脉张力障碍，表现为张力增高。其分子机制研究发现虽然高同型半胱氨酸血症大鼠冠状动脉平滑肌SOCE引发的张力增加但SOCE关键蛋白表达并不增加。进一步研究发现BKCa分子表达增加。BKCa表达增加是TRPP2-STIM1 复合物增强的代偿结果。本研究科学意义在于1、阐明心脏缺血性疾病冠脉张力的改变与储存钙通道(SOCE)的关系2、阐明冠脉张力的改变调节因素和代偿因素3、阐明心脏缺血性疾病冠脉结构变化 4、调节SOCE作用复合物的表达。

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