title: Rho-kinase is involved in macrophage-mediated formation of coronary vascular lesions in pigs in vivo.
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.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Miyata
authors.forename: H
authors.initials: H
authors.lastname: Shimokawa
authors.forename: T
authors.initials: T
authors.lastname: Kandabashi
authors.forename: T
authors.initials: T
authors.lastname: Higo
authors.forename: K
authors.initials: K
authors.lastname: Morishige
authors.forename: Y
authors.initials: Y
authors.lastname: Eto
authors.forename: K
authors.initials: K
authors.lastname: Egashira
authors.forename: K
authors.initials: K
authors.lastname: Kaibuchi
authors.forename: A
authors.initials: A
authors.lastname: Takeshita
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000284:Administration, Oral; D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D003331:Coronary Vessels / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D013552:Swine; D054460:rho-Associated Kinases
chemical_list: D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C049347:fasudil