CTRP9通过巨噬细胞AdipoR1对急性冠脉综合征粥样硬化斑块易损性的作用及机制研究

Acute coronary syndrome is the main cause of unfavorable prognosis with cardiovascular disease. Macrophage inflammation plays a key role in the rupture of vulnerable plaques of acute coronary syndrome. C1q/TNF-related protein 9 (CTRP9) is a newly discovered adipocytokine which plays important roles in regulating metabolism, protecting myocardium, relaxing vessel and improving vascular function. Our previous studies have demonstrated that CTRP9 protected against atherosclerotic vulnerable plaques by reducing pro-inflammatory cytokines in macrophages. However, the precise mechanism is still unclear. Based on the results of the preliminary experiments, we hypothesize that CTRP9 can activate AMPK through adiopnectin receptor 1 in macrophages, then attenuate atherosclerotic plaque inflammation in macrophages and thereby inhibit the apoptosis and calcification of vascular smooth muscle cells. To verify our hypothesis, we aim to establish a vulnerable carotid plaque model in CTRP9-/-ApoE-/- mice and AdipoR1Mø-/-ApoE-/- mice, and construct macrophage and vascular smooth muscle cell co-culture systems in vitro. We further investigate the regulatory mechanisms of CTRP9 on the molecular, cellular and animal level in stabilizing atherosclerotic vulnerable plaques, so as to provide a new regulated target and scientific basis for preventing and treating acute coronary syndrome.

急性冠脉综合征（ACS）是心血管疾病不良预后的主要原因，巨噬细胞炎症反应是ACS易损斑块破裂的关键。C1q/肿瘤坏死因子相关蛋白9（CTRP9）是新型脂肪细胞因子，在调节代谢、保护心肌、舒张血管及改善内皮功能等方面发挥重要作用。我们前期研究显示，CTRP9可增加动脉粥样硬化斑块稳定性并可抑制斑块内巨噬细胞炎症反应，但其机制不清。基于预实验结果，本课题组提出CTRP9主要通过巨噬细胞AdipoR1调控ACS斑块稳定性，由AMPK信号介导，抑制斑块内巨噬细胞炎症反应，从而抑制平滑肌细胞凋亡、钙化。拟建立CTRP9-/-ApoE-/-小鼠和AdipoR1Mø-/-ApoE-/-小鼠斑块易损和破裂模型，并于体外构建巨噬细胞与平滑肌细胞共培养体系，从分子、细胞、动物多层次探讨CTRP9对ACS易损斑块的调控机制，该研究结果将为ACS的防治提供新的调控靶点和科学依据。

CTRP9 是一种与脂联素球状结构域高度同源的脂肪细胞因子，有研究证实与脂联素相比，CTRP9在心血管系统高度表达，且在缺血性心肌病和血管舒张等研究领域与脂联素发挥类似的功能。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促进巨噬细胞M1表型极化2．CTRP9预处理巨噬细胞-平滑肌细胞共培养体系，加剧平滑肌细胞的增殖及凋亡3.CTRP9通过AdipoR1/AMPK通路促进胆固醇流出抑制巨噬细胞凋亡4.CTRP9通过促进自噬减轻棕榈酸对心肌细胞氧化应激水平5.CTRP9通过LKB1 / AMPK信号通路发挥抗心肌脂毒性和抑制心肌肥大的作用.这些研究结果提示，CTRP9 可能通过改变巨噬细胞表型、促进巨噬细胞内胆固醇流出影响动脉粥样硬化斑块的稳定性；通过促进自噬降低心肌细胞的氧化应激水平，改善心肌脂毒性，提示CTRP9的心肌保护作用，为心血管疾病的研究提供了新靶点。