Miyata K, Shimokawa H, Kandabashi T, Higo T, Morishige K, Eto Y, Egashira K, Kaibuchi K, Takeshita A
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Arterioscler Thromb Vasc Biol. 2000 Nov;20(11):2351-8. doi: 10.1161/01.atv.20.11.2351.
We have previously shown that long-term treatment with an inflammatory cytokine from the adventitia causes the development of coronary vascular lesions, with the accumulation of macrophages. Recent studies in vitro have suggested that small G-protein Rho and its effector, Rho-kinase/ROK/ROCK, may be the key molecules for various cellular functions, including cell adhesion and movement. In this study, we examined whether adventitia-derived macrophages cause the formation of coronary vascular lesions in vivo and, if so, whether Rho-kinase is involved in the process. Porcine coronary segments from the adventitia were chronically treated with monocyte chemoattractant protein-1 alone, oxidized low density lipoprotein alone, or both. Vascular lesion formation (neointimal formation and development of vascular remodeling) was mostly enhanced at the coronary segment cotreated with monocyte chemoattractant protein-1 and oxidized low density lipoprotein, where the phosphorylation of myosin binding subunit of myosin phosphatase was increased, indicating an increased activity of Rho-kinase in vivo. Histological examination demonstrated that macrophages were accumulated at the adventitia and thereafter migrated into the vascular wall. Long-term oral treatment with fasudil, which is metabolized to a specific Rho-kinase inhibitor (hydroxyfasudil) after oral absorption, markedly inhibited the myosin binding subunit phosphorylation, the macrophage accumulation and migration, and the coronary lesion formation in vivo. These results indicate that Rho-kinase is involved in macrophage-mediated formation of coronary vascular lesions in our porcine model in vivo.
我们之前已经表明，外膜来源的炎性细胞因子长期治疗会导致冠状动脉血管病变的发展，并伴有巨噬细胞的积聚。最近的体外研究表明，小G蛋白Rho及其效应器Rho激酶/ROK/ROCK可能是包括细胞黏附和运动在内的各种细胞功能的关键分子。在本研究中，我们检测了外膜来源的巨噬细胞是否会在体内导致冠状动脉血管病变的形成，如果是，Rho激酶是否参与了这一过程。分别用单核细胞趋化蛋白-1、氧化型低密度脂蛋白单独处理或两者共同处理猪冠状动脉外膜段。在单核细胞趋化蛋白-1和氧化型低密度脂蛋白共同处理的冠状动脉段，血管病变形成（内膜增生和血管重塑的发展）大多增强，其中肌球蛋白磷酸酶的肌球蛋白结合亚基的磷酸化增加，表明体内Rho激酶活性增加。组织学检查显示巨噬细胞在外膜积聚，随后迁移到血管壁。口服法舒地尔后长期治疗，法舒地尔口服吸收后代谢为一种特异性Rho激酶抑制剂（羟基法舒地尔），可显著抑制体内肌球蛋白结合亚基磷酸化、巨噬细胞积聚和迁移以及冠状动脉病变形成。这些结果表明，在我们的猪体内模型中，Rho激酶参与了巨噬细胞介导的冠状动脉血管病变形成。
