The regulation of Ero1-alpha in homocysteine-induced macrophage apoptosis and vulnerable plaque formation in atherosclerosis

Background and aims: Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis and plaque vulnerability. Macrophage apoptosis mediated by endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of HHcy-aggravated atherosclerosis. Endoplasmic reticulum oxidoreductase 1 alpha (Ero1 alpha) is critical for ER stress-induced apoptosis. We hypothesized that Ero1 alpha may contribute to ER-stress induced macrophage apoptosis and plaque stability in advanced atherosclerotic lesions by HHcy. Methods: Apoe(-/-) mice were maintained on drinking water containing homocysteine (Hcy, 1.8 g/L) to establish HHcy atherosclerotic models. The role of Ero1 alpha in atherosclerotic plaque stability, macrophage apoptosis and ER stress were monitored in the plaque of aortic roots in HHcy Apoe(-/-) mice with or without silence or overexpression of Ero1 alpha through lentivirus. Mouse peritoneal macrophages were used to confirm the regulation of Ero1 alpha on ER stress dependent apoptosis in the presence of HHcy. Results: Atherosclerotic plaque vulnerability and macrophage apoptosis were promoted in Apoe(-/-) mice by high Hcy diet, accompanied by the upregulation of Ero1 alpha expression and ER stress. Inhibition of Ero1 alpha prevented macrophage apoptosis and atherosclerotic plaque vulnerability, and vice versa. Consistently, in mouse peritoneal macrophages, ER stress and apoptosis were attenuated by Ero1 alpha deficiency, but enhanced by Ero1 alpha overexpression. Conclusions: Hcy, via upregulation of Ero1 alpha expression, activates ER stress-dependent macrophage apoptosis to promote vulnerable plaque formation in atherosclerosis. Ero1 alpha may be a potential therapeutic target for atherosclerosis induced by Hcy.

Automated summary

Hyperhomocysteinemia aggravates atherosclerosis and plaque vulnerability through endoplasmic reticulum oxidoreductase 1 alpha, which is critical in ER stress-induced macrophage apoptosis and plaque stability.