Vascular smooth muscle cell c-Fos is critical for foam cell formation and atherosclerosis.

Guolin Miao, Xi Zhao, Siu-Lung Chan, Lijun Zhang, Yaohua Li, Yuke Zhang, Lijun Zhang, Beibei Wang

Metabolism: clinical and experimental 2022 Jul

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Hyperlipidemia-induced vascular smooth muscle cell (VSMC)-derived foam cell formation is considered a crucial event in the development of atherosclerosis. Since c-Fos emerges as a key modulator of lipid metabolism, we investigated whether c-Fos plays a role in hyperlipidemia-induced VSMC-derived foam cell formation and atherosclerosis. c-Fos expression was observed in VSMCs in atherosclerotic plaques from patients and western diet-fed atherosclerosis-prone LDLR-/- and ApoE-/- mice by immunofluorescence staining. To ascertain c-Fos's function in atherosclerosis development, VSMC-specific c-Fos deficient mice in ApoE-/- background were established. Western diet-fed c-FosVSMCKOApoE-/- mice exhibited a significant reduction of atherosclerotic lesion formation as measured by hematoxylin and eosin staining, accompanied by decreased lipid deposition within aortic roots as determined by Oil red O staining. Primary rat VSMCs were isolated to examine the role of c-Fos in lipid uptake and foam cell formation. oxLDL stimulation resulted in VSMC-derived foam cell formation and elevated intracellular mitochondrial reactive oxygen species (mtROS), c-Fos and LOX-1 levels, whereas specific inhibition of mtROS, c-Fos or LOX-1 lessened lipid accumulation in oxLDL-stimulated VSMCs. Mechanistically, oxLDL acts through mtROS to enhance transcription activity of c-Fos to facilitate the expression of LOX-1, exerting a feedforward mechanism with oxLDL to increase lipid uptake and propel VSMC-derived foam cell formation and atherogenesis. Our study demonstrates a fundamental role of mtROS/c-Fos/LOX-1 signaling pathway in promoting oxLDL uptake and VSMC-derived foam cell formation during atherosclerosis. c-Fos may represent a promising therapeutic target amenable to clinical translation in the future. Copyright © 2022. Published by Elsevier Inc.

Citation

Guolin Miao, Xi Zhao, Siu-Lung Chan, Lijun Zhang, Yaohua Li, Yuke Zhang, Lijun Zhang, Beibei Wang. Vascular smooth muscle cell c-Fos is critical for foam cell formation and atherosclerosis. Metabolism: clinical and experimental. 2022 Jul;132:155213