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

Molecular Medicine

Research Article

Ying Lv¹  Yuwu Chen¹  Sining Hu¹  Xiaoxuan Bai¹  Ming Zeng¹  Haibo Jia¹  Xiuzhu Weng¹  Minghao Liu¹  Xinyu Dai¹  Xing Luo¹  Jinyu Qi¹  Chen Zhao¹  Xiaoyi Bao¹  Shan Zhang¹  Ji Li¹  Ying Zhang² 

[1] Department of Cardiology, The 2nd affiliated Hospital of Harbin Medical University, 150001, Harbin, People’s Republic of China;National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, 150001, Harbin, People’s Republic of China;Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Jiamusi University, 154007, Jiamusi, People’s Republic of China;

关键词: Atherosclerosis;    Calcium disorder;    Homocysteine;    Hyperhomocysteinemia;    Inflammasome;    Pyroptosis;    Risk factor;   

DOI  :  10.1186/s10020-023-00656-z

 received in 2022-11-29, accepted in 2023-04-19,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundElevated 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.MethodsA hyperhomocysteinemia atherosclerotic model with ApoE−/− 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.ResultsWe 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 consequently contributed to calcium disorder. Furthermore, the endoplasmic reticulum stress inhibitor, 4PBA, the calcium chelator, BAPTA, and calcium channel inhibitor, 2-APB significantly improved macrophage pyroptosis.ConclusionHomocysteine accelerates atherosclerosis progression by enhancing macrophages pyroptosis via promoting endoplasmic reticulum stress, endoplasmic reticulum-mitochondria coupling, and disturbing of calcium disorder.

【 授权许可】

CC BY   
© The Author(s) 2023

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