Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China; Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, China.
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
Metabolism. 2022 Jul;132:155213. doi: 10.1016/j.metabol.2022.155213. Epub 2022 May 2.
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-FosApoE 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.
高血脂诱导的血管平滑肌细胞（VSMC）源性泡沫细胞形成被认为是动脉粥样硬化发展的关键事件。由于 c-Fos 作为脂质代谢的关键调节剂出现，我们研究了 c-Fos 是否在高血脂诱导的 VSMC 源性泡沫细胞形成和动脉粥样硬化中发挥作用。
免疫荧光染色显示，患者动脉粥样硬化斑块和西方饮食喂养的动脉粥样硬化易感 LDLR 和 ApoE 小鼠的 VSMCs 中存在 c-Fos 表达。为了确定 c-Fos 在动脉粥样硬化发展中的作用，我们在 ApoE 背景下建立了 VSMC 特异性 c-Fos 缺陷小鼠。与对照组相比，西方饮食喂养的 c-FosApoE 小鼠的动脉粥样硬化病变形成显著减少，主动脉根部油红 O 染色显示脂质沉积减少。分离原代大鼠 VSMCs 以研究 c-Fos 在脂质摄取和泡沫细胞形成中的作用。oxLDL 刺激导致 VSMC 源性泡沫细胞形成和细胞内线粒体活性氧（mtROS）、c-Fos 和 LOX-1 水平升高，而特异性抑制 mtROS、c-Fos 或 LOX-1 可减少 oxLDL 刺激的 VSMCs 中的脂质积累。机制上，oxLDL 通过 mtROS 增强 c-Fos 的转录活性，促进 LOX-1 的表达，通过 oxLDL 发挥正反馈机制增加脂质摄取并促进 VSMC 源性泡沫细胞形成和动脉粥样硬化发生。
我们的研究表明，mtROS/c-Fos/LOX-1 信号通路在促进 oxLDL 摄取和动脉粥样硬化期间 VSMC 源性泡沫细胞形成中起基本作用。c-Fos 可能代表未来具有临床转化前景的有希望的治疗靶点。
