Ouyang Jie, Chen Shuhua, Xiang Hong, Tang Baiyi, Long Haijiao, Liu Quanjun, Qin Shiying, Zheng Xinru, Chen Alex F, Lu Hongwei
Center for Experimental Medical Research, the Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Cardiology, the Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Department of Biochemistry, School of Life Sciences of Central South University, Changsha, Hunan, China.
Biochem Pharmacol. 2025 Nov;241:117164. doi: 10.1016/j.bcp.2025.117164. Epub 2025 Jul 11.
Disrupted mitochondria-associated endoplasmic reticulum membrane (MAM) homeostasis is closely linked to obesity-related diseases and insulin resistance pathogenesis. The formation of foam cells with classically activated lipid uptake by macrophages is an important mechanism in the progression of atherosclerosis. This study investigated the effects of the MAM interface anchor protein, phosphofurin acidic cluster sorting protein 2 (PACS2), on atherosclerosis. MAM expansion, accompanied by elevated PACS2 expression, was observed in the plaques of atherosclerotic mice and oxidized low-density lipoprotein (Ox-LDL)-treated macrophages. Furthermore, PACS2 knockout in mice significantly reduced atherosclerotic plaque formation and improved the lipid profiles. PACS2 activated the ROS-PPARγ-CD36 signaling pathway, which drove lipid uptake in macrophages. Notably, the activation of this signaling pathway also increased PACS2 production. PACS2 knockout or silencing disrupted the positive feedback loop between PACS2 and ROS-PPARγ-CD36, preventing the proatherogenic phenotypic changes in macrophages. These findings establish the causal role of PACS2 in atherosclerosis related to modulating the macrophage phenotype and highlight its potential as a therapeutic target in atherosclerosis-driven cardiovascular diseases.
线粒体相关内质网膜（MAM）稳态破坏与肥胖相关疾病及胰岛素抵抗发病机制密切相关。巨噬细胞通过经典激活的脂质摄取形成泡沫细胞是动脉粥样硬化进展的重要机制。本研究探讨了MAM界面锚定蛋白磷蛋白酸性簇分选蛋白2（PACS2）对动脉粥样硬化的影响。在动脉粥样硬化小鼠斑块和氧化低密度脂蛋白（Ox-LDL）处理的巨噬细胞中观察到MAM扩张，同时PACS2表达升高。此外，小鼠中PACS2基因敲除显著减少动脉粥样硬化斑块形成并改善脂质谱。PACS2激活ROS-PPARγ-CD36信号通路，该通路驱动巨噬细胞摄取脂质。值得注意的是，该信号通路的激活也增加了PACS2的产生。PACS2基因敲除或沉默破坏了PACS2与ROS-PPARγ-CD36之间的正反馈回路，阻止了巨噬细胞的促动脉粥样硬化表型改变。这些发现确立了PACS2在与调节巨噬细胞表型相关的动脉粥样硬化中的因果作用，并突出了其作为动脉粥样硬化驱动的心血管疾病治疗靶点的潜力。
