脂肪细胞因子CTRP9对动脉粥样硬化斑块稳定性的影响及机制研究

Atherosclerotic vulnerable plaque, the pathological basis of acute cardiovascular events, is a threat to the life of CHD patients. CTRP9, a newly discovered adipocytokine and the closest paralog of APN, has been found to play an important role in the development of cardiovascular diseases. We have successfully established the vulnerable plaque and gene intervention mode. We put forward a hypothesis that the gene therapy of CTRP9 can effectively inhibits the monocyte recruitment and the foam cell formation, inhibiting the inflammatory reaction, and then stabilize the vulnerable plaques refer to the latest research progress.We intend to build the recombinant lentivirus of CTRP9 and CTRP9-siRNA, transfect them into AS rat model in vivo, through the detection of relevant indicators. We aim to research ① CTRP9 expression and its role in the development of atherosclerosis; ②whether CTRP9 exerts its effects through regulating the function of vascular endothelial cells、macrophages and smooth muscle cells; ③the interaction between CTRP9 and APN in the process of atherosclerosis, so as to clarify the role of CTRP9 in atherosclerosis development and plaque stability, and reveal the underlying mechanisms. To provide a reliable theoretical and experimental evidence for the hypothesis that CTRP9 is a new predictor of vulnerable plaques and a drug intervention target for AS.

AS易损斑块为急性心血管事件的病理基础，严重威胁着病人的生命和生活质量。CTRP9为最近发现的与APN结构最同源的脂肪细胞因子，在心血管疾病发生发展多个环节发挥重要作用。我们已经建立了易损斑块和基因干预模型，在参阅最新研究进展的基础上提出针对CTRP9的基因治疗能有效抑制单核细胞募集和泡沫细胞形成，抑制炎症反应，进而稳定AS易损斑块的假说。我们拟构建CTRP9和CTRP9-siRNA慢病毒，体内转染AS鼠模型,通过对相关指标的检测研究①CTRP9在斑块内的表达及其对AS发生发展及斑块稳定性的影响，②CTRP9是否通过调节内皮细胞、巨噬细胞及平滑肌细胞功能进而影响AS进程，③CTRP9与APN在动脉粥样硬化中的相互作用；阐明CTRP9在AS发生发展及斑块稳定性中的作用及机制，为CTRP9作为AS易损斑块新的预测指标及药物干预靶点提供可靠的理论及实验依据。

CTRP9是一种新发现的脂肪细胞因子，与脂联素球状结构域高度同源,已有研究证实CTRP9在缺血性心肌病和血管舒张等研究领域与脂联素存在类似的功能。此外，脂联素还具有抗炎，抗动脉粥样硬化，稳定斑块的作用。本研究旨在通过体内和体外实验观察CTRP9与动脉粥样硬化斑块稳定性的关系。结果发现：（1）CTRP9过表达组斑块内脂滴较对照组减少；斑块内胶原含量较对照组高；斑块内巨噬细胞较对照组减少，平滑肌细胞较对照组增加；（2）CTRP9过表达组斑块内局部炎症较对照组降低，表现在TNF-α和MCP-1水平的降低；（3）体外培养RAW 264.7细胞诱导的动脉粥样硬化模型，CTRP9组TNF-α和MCP-1蛋白水平均较对照组降低。这些研究结果提示，CTRP9可能通过减少局部巨噬细胞炎症表达，抑制炎症细胞浸润，降低斑块易损性，从而增加动脉粥样硬化斑块的稳定性等作用。