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 1α (Ero1α) is critical for ER stress-induced apoptosis. We hypothesized that Ero1α 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 Ero1α 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 Ero1α through lentivirus. Mouse peritoneal macrophages were used to confirm the regulation of Ero1α 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 Ero1α expression and ER stress. Inhibition of Ero1α prevented macrophage apoptosis and atherosclerotic plaque vulnerability, and vice versa. Consistently, in mouse peritoneal macrophages, ER stress and apoptosis were attenuated by Ero1α deficiency, but enhanced by Ero1α overexpression.

Conclusions

Hcy, via upregulation of Ero1α expression, activates ER stress-dependent macrophage apoptosis to promote vulnerable plaque formation in atherosclerosis. Ero1α may be a potential therapeutic target for atherosclerosis induced by Hcy.

中文翻译：

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Ero1-α在同型半胱氨酸诱导的巨噬细胞凋亡和动脉粥样硬化易损斑块形成中的调控

背景和目标

高同型半胱氨酸血症 (HHcy) 是动脉粥样硬化和斑块易损性的独立危险因素。由内质网（ER）应激介导的巨噬细胞凋亡在 HHcy 加重的动脉粥样硬化的发病机制中起重要作用。内质网氧化还原酶 1α (Ero1α) 对内质网应激诱导的细胞凋亡至关重要。我们假设 Ero1α 可能通过 HHcy 促进 ER 应激诱导的巨噬细胞凋亡和晚期动脉粥样硬化病变中的斑块稳定性。

方法

Apoe ^-/-小鼠维持在含有高半胱氨酸（Hcy，1.8 g/L）的饮用水中以建立 HHcy 动脉粥样硬化模型。在 HHcy Apoe ^-/-小鼠主动脉根斑块中监测 Ero1α 在动脉粥样硬化斑块稳定性、巨噬细胞凋亡和内质网应激中的作用，无论是否沉默或通过慢病毒过表达 Ero1α。小鼠腹腔巨噬细胞用于确认在 HHcy 存在下 Ero1α 对 ER 应激依赖性细胞凋亡的调节。

结果

高 Hcy 饮食促进了Apoe ^-/-小鼠的动脉粥样硬化斑块易损性和巨噬细胞凋亡，伴随着 Ero1α 表达的上调和 ER 应激。抑制 Ero1α 可防止巨噬细胞凋亡和动脉粥样硬化斑块易损性，反之亦然。一致地，在小鼠腹膜巨噬细胞中，ER 应激和细胞凋亡因 Ero1α 缺乏而减弱，但因 Ero1α 过表达而增强。

结论

Hcy 通过上调 Ero1α 表达，激活 ER 应激依赖性巨噬细胞凋亡，促进动脉粥样硬化中易损斑块的形成。Ero1α 可能是 Hcy 诱导的动脉粥样硬化的潜在治疗靶点。