Homocysteine promotes atherosclerosis through macrophage pyroptosis via endoplasmic reticulum stress and calcium disorder

作者：Shan Zhang, Ying Lv, Xing Luo, Xiuzhu Weng, Jinyu Qi, Xiaoxuan Bai, Chen Zhao, Ming Zeng, Xiaoyi Bao, Xinyu Dai, Ying Zhang, Yuwu Chen, Minghao Liu, Sining Hu, Ji Li, J. Haibo · 发表于：Molecular Medicine · 年份：2023 · DOI：10.1186/s10020-023-00656-z · 被引用次数：78 · 研究领域：Inflammasome and immune disorders、Folate and B Vitamins Research、Endoplasmic Reticulum Stress and Disease

BACKGROUND: Elevated plasma homocysteine levels, known as hyperhomocysteinemia, have been identified as an independent risk factor for atherosclerosis and related cardiovascular diseases. Macrophage pyroptosis-mediated inflammation is crucial in the development of atherosclerosis, but the underlying mechanisms remain unclear. METHODS: mice fed with a high-methionine diet was constructed to investigate the role of plasma homocysteine in atherosclerosis. THP-1-derived macrophages were used to investigate the mechanisms by which Hcy regulates pyroptosis. RESULTS: We found that hyperhomocysteinemia resulted in larger atherosclerotic plaques and more secretion of inflammatory cytokines, while these effects were attenuated in Caspase-1 knockdown mice. Likewise, in vitro experiments demonstrated that treatment of macrophages with homocysteine resulted in NLRP3 inflammasome activation and pyroptosis, as evidenced by cleavage of Caspase-1, production of downstream IL-1β, elevation of lactate dehydrogenase activity, and extensive propidium iodide-positive staining of cells. These were all inhibited by Caspase-1 inhibitor. In addition, excessive generation of reactive oxygen species was associated with mitochondrial dysfunction, characterized by loss of mitochondrial membrane potential and ATP synthesis. Moreover, further experiments revealed that homocysteine induced endoplasmic reticulum stress, enhanced communication between the endoplasmic reticulum and mitochondria, and consequentl...