Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Arterioscler Thromb Vasc Biol. 2010 Oct;30(10):1925-32. doi: 10.1161/ATVBAHA.110.206094. Epub 2010 Jul 22.
To elucidate whether and how the endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP) pathway in macrophages is involved in the rupture of atherosclerotic plaques.
Increases in macrophage-derived foam cell death in coronary atherosclerotic plaques cause the plaque to become vulnerable, thus resulting in acute coronary syndrome. The ER stress-CHOP/growth arrest and DNA damage-inducible gene-153 (GADD153) pathway is induced in the macrophage-derived cells in atherosclerotic lesions and is involved in plaque formation. However, the role of CHOP in the final stage of atherosclerosis has not been fully elucidated. Many CHOP-expressing macrophages showed apoptosis in advanced ruptured atherosclerotic lesions in wild-type mice, whereas few apoptotic cells were observed in Chop(-/-) mice. The rupture of atherosclerotic plaques was significantly reduced in high cholesterol-fed Chop(-/-)/Apoe(-/-) mice compared with Chop(+/+)/Apoe(-/-) mice. Furthermore, using mice that underwent bone marrow transplantation, we showed that expression of CHOP in macrophages significantly contributes to the formation of ruptures. By using primary cultured macrophages, we further showed that unesterified free cholesterol derived from incorporated denatured low-density lipoprotein was accumulated in the ER and induced ER stress-mediated apoptosis in a CHOP-Bcl2-associated X protein (Bax) pathway-dependent manner.
The ER stress-CHOP-Bax-mediated apoptosis in macrophages contributes to the instability of atherosclerotic plaques.
阐明内质网（ER）应激-C/EBP 同源蛋白（CHOP）通路在巨噬细胞中是否以及如何参与动脉粥样硬化斑块的破裂。
冠状动脉粥样硬化斑块中巨噬细胞源性泡沫细胞死亡的增加导致斑块变得脆弱，从而导致急性冠状动脉综合征。在动脉粥样硬化病变中的巨噬细胞源性细胞中诱导 ER 应激-CHOP/生长停滞和 DNA 损伤诱导基因 153（GADD153）通路，并参与斑块形成。然而，CHOP 在动脉粥样硬化的最后阶段的作用尚未完全阐明。在野生型小鼠的晚期破裂性动脉粥样硬化病变中，许多表达 CHOP 的巨噬细胞显示出凋亡，而在 Chop(-/-)小鼠中则很少观察到凋亡细胞。与 Chop(+/+)/Apoe(-/-)小鼠相比，高胆固醇喂养的 Chop(-/-)/Apoe(-/-)小鼠的动脉粥样硬化斑块破裂明显减少。此外，通过使用进行骨髓移植的小鼠，我们表明巨噬细胞中 CHOP 的表达显著促进了破裂的形成。通过使用原代培养的巨噬细胞，我们进一步表明，掺入变性的低密度脂蛋白衍生的未酯化游离胆固醇在内质网中积累，并以 CHOP-Bcl2 相关 X 蛋白（Bax）通路依赖性方式诱导 ER 应激介导的细胞凋亡。
巨噬细胞中的 ER 应激-CHOP-Bax 介导的细胞凋亡导致动脉粥样硬化斑块的不稳定性。
