Cigarette tar accelerates atherosclerosis progression via RIPK3-dependent necroptosis mediated by endoplasmic reticulum stress in vascular smooth muscle cells

作者：Xiaoxuan Bai, Ying Wang, Xing Luo, Xiaoyi Bao, Xiuzhu Weng, Yuwu Chen, Shan Zhang, Ying Lv, Xinyu Dai, Ming Zeng, Dan Yang, Sining Hu, Ji Li, Yong Ji, Haibo Jia, Bo Yu · 发表于：Cell Communication and Signaling · 年份：2024 · DOI：10.1186/s12964-024-01480-6 · 被引用次数：18 · 研究领域：Cell death mechanisms and regulation、Autophagy in Disease and Therapy、Phagocytosis and Immune Regulation

Abstract Background Tar is the main toxic of cigarettes, and its effect on atherosclerosis progression and the underlying mechanisms remain largely unknown. Vascular smooth muscle cells (VSMCs) play a key role in atherogenesis and plaque vulnerability. The present study sought to investigate the mechanism of atherosclerosis progression through tar-induced VSMC necroptosis, a recently described form of necrosis. Methods The effect of tar on atherosclerosis progression and VSMC necroptosis was examined in ApoE −/− mice and cultured VSMCs. The role of necroptosis in tar-induced plaque development was evaluated in RIPK3-deletion mice (ApoE −/− RIPK3 −/− ). The key proteins of necroptosis in carotid plaques of smokers and non-smokers were also examined. Quantitative proteomics of mice aortas was conducted to further investigate the underlying mechanism. Pharmacological approaches were then applied to modulate the expression of targets to verify the regulatory process of tar-induced necroptosis. Results Tar administration led to increased atherosclerotic plaque area and reduced collagen and VSMCs in ApoE −/− mice. The expression of RIPK1、RIPK3、and MLKL in VSMCs of plaques were all increased in tar-exposed mice and smokers. RIPK3 deletion protected against VSMC loss and plaque progression stimulated by tar. In mechanistic studies, quantitative proteomics analysis of ApoE −/− mice aortas suggested that tar triggered endoplasmic reticulum (ER) stress. PERK-eIF2α-CHOP axis was activate...