Rho-kinase is involved in macrophage-mediated formation of coronary vascular lesions in pigs in vivo

Kenji Miyata, Hiroaki Shimokawa, Tadashi Kandabashi, Taiki Higo, Kunio Morishige, Yasuhiro Eto, Kensuke Egashira, Kozo Kaibuchi, Akira Takeshita

Research output: Contribution to journalArticle

169 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2351-2358
Number of pages8
JournalArteriosclerosis, thrombosis, and vascular biology
Volume20
Issue number11
DOIs
Publication statusPublished - 2000

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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