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(Circulation Research. 2004;94:46.)
© 2004 American Heart Association, Inc.

Molecular Medicine

Long-Term Treatment With a Specific Rho-Kinase Inhibitor Suppresses Cardiac Allograft Vasculopathy in Mice

Tsuyoshi Hattori, Hiroaki Shimokawa, Midoriko Higashi, Junko Hiroki, Yasushi Mukai, Kozo Kaibuchi, Akira Takeshita

From the Department of Cardiovascular Medicine (T.H., H.S., M.H., J.H., Y.M., A.T.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; the Department of Cell Pharmacology (K.K.), Nagoya University Graduate School of Medicine, Nagoya, Japan; and Kyushu University COE Program on Lifestyle-Related Diseases (H.S.), Fukuoka, Japan.

Correspondence to Hiroaki Shimokawa, MD, PhD, Department of Cardiovascular Medicine Kyushu University Graduate School of Medical Sciences Fukuoka, Japan 812-8582. E-mail shimo{at}cardiol.med.kyushu-u.ac.jp

Cardiac allograft vasculopathy (CAV) continues to be a major cause of late graft failure after cardiac transplantation. We have demonstrated that Rho-kinase, an effector of the small GTPase Rho, plays an important role in the pathogenesis of arteriosclerosis. In this study, we examined whether the Rho-kinase–mediated pathway is also involved in the pathogenesis of CAV using a specific Rho-kinase inhibitor and a dominant-negative Rho-kinase. Hearts from AKR mice were heterotopically transplanted to C3H/He (allograft) or AKR mice (isograft), and the effects of long-term oral treatment with fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil, on CAV were examined at 2 and 4 weeks after the transplantation. Coronary remodeling in the allografts characterized by intimal thickening and perivascular fibrosis was dose-dependently suppressed in the fasudil group compared with the control group (P<0.01, n=9 to 10). The inhibitory effects of hydroxyfasudil were mimicked by in vivo gene transfer of dominant-negative Rho-kinase (P<0.05, n=4). Among the proinflammatory cytokines examined, those of macrophage migration inhibitory factor, interferon-, and transforming growth factor-ß1 were upregulated in the control group and were dose-dependently inhibited in the fasudil group (P<0.01, n=5). Vascular inflammation in the allografts, as evidenced by accumulation of inflammatory cells (macrophages and T cells), was also significantly inhibited in the fasudil group (P<0.05, n=5 to 10). These results indicate that long-term treatment with fasudil suppresses CAV in mice, suggesting that Rho-kinase is an important therapeutic target for the prevention of CAV.

Key Words: arteriosclerosis • cytokines • transplantation

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