Jiacheng Chen, Li Jiang, Fengying Zhang, Yan Luo, Bibiao Shen, Zhao Pan, Ping Zhang, ZhengYang Yuan, Yongjun Chen, Yangzhi Xie
HCAR2 activation is associated with enhanced macrophage efferocytosis and reduced atherosclerotic plaque burden, correlating with Ca2+/cAMP-mediated AMPK/ABCA1 pathway engagement. These findings suggest a potential mechanistic link between HCAR2 and efferocytosis, but the causal relationship remains to be established. Notably, the in vivo role of the ABCA1 pathway was not validated in this study.
BACKGROUND: Atherosclerotic plaque progression involves lipid accumulation, inflammation, and impaired efferocytosis, the macrophage mediated clearance of apoptotic cells. HCAR2, a metabolite sensing receptor highly expressed on macrophages, modulates immune metabolic responses, but its role in efferocytosis and atherosclerosis remains unclear.
METHODS: APOE-/- and bone marrow chimeric mice were fed a high fat diet and treated with HCAR2 agonist MK-6892 or vehicle. Plaque size, composition, and efferocytic activity were assessed. Primary macrophages were evaluated for efferocytosis, lipid metabolism, cytokine release, and cholesterol efflux. Mechanistic studies included transcriptomics, immunoblotting, calcium imaging, and loss of function experiments.
RESULTS: Compared to APOE-/- controls, APOE-/- mice lacking HCAR2 exhibited larger atherosclerotic plaques with increased lipid deposition, reduced collagen content, decreased smooth muscle cell coverage, and impaired efferocytosis. HCAR2 activation rescued the atherosclerotic phenotype and efferocytosis. Bone marrow transplantation confirmed that hematopoietic HCAR2 deficiency aggravated atherosclerosis. An in vitro study confirmed that HCAR2 restricted foam cell formation, inhibited the release of pro-inflammatory cytokines, promoted cholesterol efflux, and enhanced efferocytic activity. Mechanistically, HCAR2 signaling increased intracellular Ca2+ and cAMP levels, activating the downstream Ca2+/CAMKK2/AMPK and PKA/LKB1/AMPK pathways, which subsequently upregulated LXRα/ABCA1 signaling. Lentiviral knockdown of ABCA1 blocked HCAR2-induced enhancement of macrophage efferocytosis, cholesterol efflux, and inflammatory regulation in vitro, indicating that ABCA1 is required for these cellular effects of HCAR2 activation.
CONCLUSION: HCAR2 activation is associated with enhanced macrophage efferocytosis and reduced atherosclerotic plaque burden, correlating with Ca2+/cAMP-mediated AMPK/ABCA1 pathway engagement. These findings suggest a potential mechanistic link between HCAR2 and efferocytosis, but the causal relationship remains to be established. Notably, the in vivo role of the ABCA1 pathway was not validated in this study.