Endoplasmic reticulum (ER) stress-induced cell death of vascular smooth muscle cells (VSMCs) is extensively involved in atherosclerotic plaque stabilization. We previously reported that nucleotide-binding oligomerization domain protein 2 (NOD2) participated in vascular homeostasis and tissue injury. However, the role and underlying mechanisms of NOD2 remain unknown in ER stress-induced cell death of VSMC during vascular diseases, including advanced atherosclerosis. Here, we report that NOD2 specifically interacted with ER stress sensor activating transcription factor 6 (ATF6) and suppressed the expression of proapoptotic transcription factor CHOP (C/EBP homologous protein) during ER stress. CHOP-positive cells were increased in neointimal lesions after femoral artery injury in NOD2-deficient mice. In particular, a NOD2 ligand, MDP, and overexpression of NOD2 decreased CHOP expression in wild-type VSMCs. NOD2 interacted with an ER stress sensor molecule, ATF6, and acted as a negative regulator for ATF6 activation and its downstream target molecule, CHOP, that regulates ER stress-induced apoptosis. Moreover, NOD2 deficiency promoted disruption of advanced atherosclerotic lesions and CHOP expression in NOD2-/- ApoE-/- mice. Our findings indicate an unsuspected critical role for NOD2 in ER stress-induced cell death.

中文翻译：

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核苷酸结合寡聚域蛋白2的缺乏会增强晚期动脉粥样硬化病变中的CHOP表达和斑块坏死。

内质网（ER）应激诱导的血管平滑肌细胞（VSMC）的细胞死亡广泛参与动脉粥样硬化斑块的稳定。我们先前曾报道核苷酸结合的寡聚域蛋白2（NOD2）参与了血管稳态和组织损伤。然而，在血管疾病（包括晚期动脉粥样硬化）期间，ERD诱导的VSMC细胞死亡中，NOD2的作用和潜在机制仍然未知。在这里，我们报告说，NOD2与内质网应激传感器激活转录因子6（ATF6）特异性相互作用，并抑制内质网应激期间促凋亡转录因子CHOP（C / EBP同源蛋白）的表达。NOD2缺陷小鼠股动脉损伤后新内膜病变中CHOP阳性细胞增加。特别是NOD2配体MDP NOD2的过度表达降低了野生型VSMC中CHOP的表达。NOD2与ER应激传感器分子ATF6相互作用，并充当ATF6激活的负调节剂及其下游靶分子CHOP，后者调节ER应激诱导的细胞凋亡。此外，NOD2缺乏促进了NOD2-/-ApoE-/-小鼠晚期动脉粥样硬化病变的破坏和CHOP表达。我们的发现表明，NOD2在内质网应激诱导的细胞死亡中发挥了不可预知的关键作用。NOD2缺乏促进NOD2-/-ApoE-/-小鼠晚期动脉粥样硬化病变的破坏和CHOP表达。我们的发现表明，NOD2在内质网应激诱导的细胞死亡中发挥了不可预知的关键作用。NOD2缺乏促进了NOD2-/-ApoE-/-小鼠晚期动脉粥样硬化病变的破坏和CHOP表达。我们的发现表明，NOD2在内质网应激诱导的细胞死亡中发挥了不可预知的关键作用。