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PACS2 initiates foam cell formation in macrophages through the ROS-PPARγ-CD36 positive feedback loop
Jie Ouyang1, Shuhua Chen2, Hong Xiang3
1Center 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.
Abstract:
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.
Insights
Phosphofurin acidic cluster sorting protein 2 (PACS2) drives atherosclerosis by promoting lipid uptake in macrophages. Inhibiting PACS2 disrupts this process, offering a potential therapeutic target for cardiovascular diseases.
Area of Science:
- Mitochondrial biology
- Cellular lipid metabolism
- Cardiovascular disease research
Background:
- Mitochondria-associated endoplasmic reticulum membrane (MAM) dysfunction is linked to obesity and insulin resistance.
- Foam cell formation via macrophage lipid uptake drives atherosclerosis progression.
Purpose of the Study:
- To investigate the role of phosphofurin acidic cluster sorting protein 2 (PACS2) in atherosclerosis.
- To elucidate the molecular mechanisms by which PACS2 influences macrophage phenotype and lipid metabolism.
Main Methods:
- Examined MAM expansion and PACS2 expression in atherosclerotic mouse plaques and macrophages treated with oxidized low-density lipoprotein (Ox-LDL).
- Utilized PACS2 knockout mice to assess its impact on atherosclerosis development and lipid profiles.
- Investigated the ROS-PPARγ-CD36 signaling pathway activation by PACS2 and its feedback loop.
Main Results:
- Elevated PACS2 expression and MAM expansion were observed in atherosclerotic lesions and Ox-LDL-treated macrophages.
- PACS2 knockout mice showed reduced atherosclerotic plaque formation and improved lipid profiles.
- PACS2 was found to activate the ROS-PPARγ-CD36 pathway, enhancing macrophage lipid uptake and creating a positive feedback loop for PACS2 production.
Conclusions:
- PACS2 plays a causal role in atherosclerosis by modulating macrophage phenotype and promoting lipid accumulation.
- Disruption of the PACS2-mediated positive feedback loop prevents proatherogenic changes in macrophages.
- PACS2 represents a potential therapeutic target for atherosclerosis and related cardiovascular diseases.
