Department of Metabolic Diseases, Center for Metabolic Diseases, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Circulation. 2011 Aug 16;124(7):830-9. doi: 10.1161/CIRCULATIONAHA.110.014050. Epub 2011 Aug 1.
The processes of arteriosclerosis, including atherosclerosis and vascular remodeling, are affected by interactions among numerous biological pathways such as responses to inflammation, oxidative stress, and endoplasmic reticulum stress. C/EBP homologous protein (CHOP), which is well known to induce cellular apoptosis in response to severe endoplasmic reticulum stress, is reportedly upregulated in plaque lesions.
We examined the effects of CHOP deficiency on 2 types of arteriosclerosis: cuff injury-induced neointimal formation and hypercholesterolemia-induced atherosclerosis. Cuff injury-induced neointimal formation was markedly inhibited in CHOP(-/-) mice with suppressed aortic expression of inflammatory factors and smooth muscle cell proliferation-related proteins. A CHOP deficiency also inhibited aortic plaque formation in hypercholesterolemic apolipoprotein E(-/-) mice with suppressed aortic expression of inflammatory factors and oxidative stress markers. Bone marrow transplantation experiments revealed that recipient CHOP deficiency significantly suppressed both cuff injury-induced neointimal formation and hypercholesterolemia-induced atherosclerotic plaque formation to a greater extent than donor CHOP deficiency, suggesting the importance of CHOP in vascular cells for arteriosclerosis progression. Furthermore, in our in vitro experiments, in not only macrophages but also endothelial and smooth muscle cell lines, endoplasmic reticulum stress inducers upregulated inflammation-, adhesion-, or smooth muscle cell proliferation-related proteins, whereas decreased CHOP expression remarkably suppressed endoplasmic reticulum stress-induced upregulation of these proteins.
In addition to the well-known signaling for apoptosis induction, CHOP may play important roles in augmenting potentially pathological biological stress responses. This noncanonical role of CHOP, especially that expressed in vascular cells, may contribute to the progression of vascular remodeling and atherosclerosis.
包括动脉粥样硬化和血管重塑在内的动脉粥样硬化过程受到许多生物途径的相互作用的影响，如炎症反应、氧化应激和内质网应激的反应。C/EBP 同源蛋白（CHOP），众所周知，它会在内质网应激严重时诱导细胞凋亡，据报道在斑块病变中上调。
我们研究了 CHOP 缺乏对 2 种动脉粥样硬化的影响：套管损伤诱导的新生内膜形成和高胆固醇血症诱导的动脉粥样硬化。CHOP（-/-）小鼠的血管炎症因子和平滑肌细胞增殖相关蛋白表达受到抑制，套管损伤诱导的新生内膜形成明显受到抑制。CHOP 缺乏也抑制了高胆固醇血症载脂蛋白 E（-/-）小鼠的主动脉斑块形成，同时抑制了主动脉炎症因子和氧化应激标志物的表达。骨髓移植实验表明，受者 CHOP 缺乏显著抑制了套管损伤诱导的新生内膜形成和高胆固醇血症诱导的动脉粥样硬化斑块形成，抑制程度大于供者 CHOP 缺乏，这表明 CHOP 在血管细胞中对动脉粥样硬化进展的重要性。此外，在我们的体外实验中，内质网应激诱导剂不仅在巨噬细胞中，而且在血管内皮细胞和平滑肌细胞系中，上调了炎症、黏附和/或平滑肌细胞增殖相关蛋白，而 CHOP 表达的减少则显著抑制了这些蛋白在内质网应激诱导下的上调。
除了众所周知的凋亡诱导信号外，CHOP 可能在增强潜在的病理性生物应激反应方面发挥重要作用。CHOP 的这种非典型作用，特别是在血管细胞中表达的作用，可能有助于血管重塑和动脉粥样硬化的进展。
