Gsα Regulates Macrophage Foam Cell Formation During Atherosclerosis

作者：Chang Ma, Yihui Li, Mi Tian, Qiming Deng, Xiaoteng Qin, Hanlin Lu, Jiangang Gao, Min Chen, Lee S. Weinstein, Mei Zhang, Peili Bu, Jianmin Yang, Yun Zhang, Cheng Zhang, Wencheng Zhang · 发表于：Circulation Research · 年份：2024 · DOI：10.1161/circresaha.123.323156 · 被引用次数：47 · 研究领域：Protein Kinase Regulation and GTPase Signaling、Glycosylation and Glycoproteins Research、Advanced Proteomics Techniques and Applications

BACKGROUND: Many cardiovascular pathologies are induced by signaling through G-protein-coupled receptors via Gsα (G protein stimulatory α subunit) proteins. However, the specific cellular mechanisms that are driven by Gsα and contribute to the development of atherosclerosis remain unclear. METHODS: High-throughput screening involving data from single-cell and bulk sequencing were used to explore the expression of Gsα in atherosclerosis. The differentially expression and activity of Gsα were analyzed by immunofluorescence and cAMP measurements. Macrophage-specific Gsα knockout (Mac-Gsα KO ) mice were generated to study the effect on atherosclerosis. The role of Gsα was determined by transplanting bone marrow and performing assays for foam cell formation, Dil-ox-LDL (oxidized low-density lipoprotein) uptake, chromatin immunoprecipitation, and luciferase reporter assays. RESULTS: ScRNA-seq showed elevated Gnas in atherosclerotic mouse aorta’s cholesterol metabolism macrophage cluster, while bulk sequencing confirmed increased GNAS expression in human plaque macrophage content. A significant upregulation of Gsα and active Gsα occurred in macrophages from human and mouse plaques. Ox-LDL could translocate Gsα from macrophage lipid rafts in short-term and promote Gnas transcription through ERK1/2 activation and C/EBPβ phosphorylation via oxidative stress in long-term. Atherosclerotic lesions from Mac-Gsα KO mice displayed decreased lipid deposition compared with those from control m...