GLP-1类似物保护心血管的新机制：通过抑制VSMCs成骨分化调控动脉钙化

Arterial calcification is one of important characters of diabetic macroangiopathy, which results in serious cardiovascular events.However it is very difficult to prevent and treat arterial calcification up till now.The important cytopathologic foundation of arterial calcification is osteoblastic differentiation of vascular smooth muscle cells(VSMCs).Our preliminary study demonstrates endogenous biological active substances -glucagon-like peptide-1 (GLP-1) analogue including exendin-4 and liragutide attenuates osteoblastic differentiation of calcifying VSMCs(CVSMCs). Our present study devote to clarify the effect and mechanism of GLP-1 analogue on arterial calcification in vitro and in vivo. Two kinds of cell model of arterial calcification will be employed to observe the effect of GLP-1 analogue's effect on osteoblastic differentiation of VSMCs. The canonical signal pathway involved in osteoblast differentiation, such as MAPK、PI3K/Akt and cAMP, will be detected after GLP-1 analogue treatment. The effect of GLP-1 analogue on transcript factor will be deterimined using luciferase reporter assay and EMSA. The effect of GLP-1 receptor on the signal pathway transduction will be determined using shRNA. The effect of GLP-1 analogue on arterial calcification in vivo will be detected in vitamin D induced arterial calcification mice model. The present project devote to reveal the new mechanism of regulating arterial calcification and discover the new target and provide a basis for treatment of arterial calcificaiton.

动脉钙化是糖尿病大血管病变重要特征且导致严重心血管事件但防治困难。血管平滑肌细胞（VSMCs）成骨分化是动脉钙化的细胞学基础。我们前期研究发现内源性生物活性物质胰高血糖素样肽1（GLP-1）的类似物exendin-4和liragutide可抑制钙化型CVSMCs成骨分化。本项目在体内和体外动脉钙化模型中探讨GLP-1类似物调控动脉钙化的作用和机制，采用2种动脉钙化细胞模型（β-甘油磷酸钠诱导VSMC和CVSMC），明确GLP-1类似物对VSMCs成骨分化的影响，观察其对成骨细胞分化经典信号通路MAPK、PI3K/Akt和cAMP等的激活，研究GLP-1类似物对转录因子的影响，用shRNA技术研究GLP-1受体在该信号转导中的作用。在动脉钙化小鼠模型中，观察GLP-1类似物体内对动脉钙化的影响及其机制。本项目在原有研究基础上，揭示动脉钙化新的调控机制，为探寻防治动脉钙化新方法提供思路和依据。