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

DOI Web Site 被引用文献7件
  • Tsuyoshi Hattori
    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.
  • Hiroaki Shimokawa
    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.
  • Midoriko Higashi
    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.
  • Junko Hiroki
    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.
  • Yasushi Mukai
    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.
  • Kozo Kaibuchi
    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.
  • 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.

抄録

<jats:p> 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 ( <jats:italic>P</jats:italic> <0.01, n=9 to 10). The inhibitory effects of hydroxyfasudil were mimicked by in vivo gene transfer of dominant-negative Rho-kinase ( <jats:italic>P</jats:italic> <0.05, n=4). Among the proinflammatory cytokines examined, those of macrophage migration inhibitory factor, interferon-γ, and transforming growth factor-β1 were upregulated in the control group and were dose-dependently inhibited in the fasudil group ( <jats:italic>P</jats:italic> <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 ( <jats:italic>P</jats:italic> <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. </jats:p>

収録刊行物

  • Circulation Research

    Circulation Research 94 (1), 46-52, 2004-01-09

    Ovid Technologies (Wolters Kluwer Health)

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