on October 30, 2003
Published online before print October 30, 2003, doi: 10.1161/01.ATV.0000105053.46994.5B
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Submitted on July 25, 2003
Accepted on October 20, 2003
Long-Term Inhibition of Rho-kinase Suppresses Neointimal Formation After Stent Implantation in Porcine Coronary Arteries -- Involvement of Multiple Mechanisms
Yasuharu Matsumoto ;
From the Department of Cardiovascular Medicine (Y.M., H.S., T.U., K.A., K.O., T.H. K.M., Y.E., Y.F., A.T.), the Department of Biomedical Engineering (T.M.), and the Department of Developmental Molecular Anatomy (K.N., Y.S.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
* To whom correspondence should be addressed. E-mail: shimo{at}cardiol.med.kyushu-u.ac.jp.
Objective--We recently demonstrated that Rho-kinase, an effector of the small GTPase Rho, is substantially involved in the pathogenesis of arteriosclerosis. In this study, we examined whether Rho-kinase is also involved in in-stent restenosis and if so, what mechanism is involved.
Methods and Results--Pigs underwent stent implantation in the left coronary artery with or without administration of fasudil (30 mg/kg/d PO), a specific Rho-kinase inhibitor, starting 2 days before the procedure for a duration of 4 weeks. At day 28, reductions in coronary diameter and neointimal formation associated with macrophage accumulation, collagen deposition, and transforming growth factor (TGF)-
1 expression were noted at the stent site, and all were significantly suppressed by fasudil. At day 7, fasudil significantly increased the frequency of TUNEL-positive apoptotic cells, while it tended to reduce that of bromodeoxyuridine-positive proliferating cells in the neointima. Western blot analysis at day 7 demonstrated that phosphorylations of the ezrin/radixin/moesin family (a marker of Rho-kinase activity in vivo) and protein expression of monocyte chemoattractant protein-1and bcl-2 were upregulated at the stent site and were significantly suppressed by fasudil.
Conclusions--These results indicate that long-term inhibition of Rho-kinase suppresses in-stent neointimal formation by multiple mechanisms, including reduced vascular inflammation, enhanced apoptosis, and decreased collagen deposition.
Key words: Rho-kinase • stents • inflammation • apoptosis • collagen
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