Long-Term Treatment With a Rho-Kinase Inhibitor Improves Monocrotaline-Induced Fatal Pulmonary Hypertension in Rats

DOI Web Site 被引用文献52件
  • Kohtaro Abe
    From the Department of Cardiovascular Medicine (K.A., H.S., K.M., T.U., K.O., Y.M., T.H.) and Pathophysiological and Experimental Pathology (Y.N., K.S.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; Kyushu University COE Program on Lifestyle-Related Diseases (H.S., K.S.), and Department of Cell Pharmacology (K.K.), Nagoya University, Graduate School of Medicine, Nagoya, Japan.
  • Hiroaki Shimokawa
    From the Department of Cardiovascular Medicine (K.A., H.S., K.M., T.U., K.O., Y.M., T.H.) and Pathophysiological and Experimental Pathology (Y.N., K.S.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; Kyushu University COE Program on Lifestyle-Related Diseases (H.S., K.S.), and Department of Cell Pharmacology (K.K.), Nagoya University, Graduate School of Medicine, Nagoya, Japan.
  • Keiko Morikawa
    From the Department of Cardiovascular Medicine (K.A., H.S., K.M., T.U., K.O., Y.M., T.H.) and Pathophysiological and Experimental Pathology (Y.N., K.S.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; Kyushu University COE Program on Lifestyle-Related Diseases (H.S., K.S.), and Department of Cell Pharmacology (K.K.), Nagoya University, Graduate School of Medicine, Nagoya, Japan.
  • Toyokazu Uwatoku
    From the Department of Cardiovascular Medicine (K.A., H.S., K.M., T.U., K.O., Y.M., T.H.) and Pathophysiological and Experimental Pathology (Y.N., K.S.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; Kyushu University COE Program on Lifestyle-Related Diseases (H.S., K.S.), and Department of Cell Pharmacology (K.K.), Nagoya University, Graduate School of Medicine, Nagoya, Japan.
  • Keiji Oi
    From the Department of Cardiovascular Medicine (K.A., H.S., K.M., T.U., K.O., Y.M., T.H.) and Pathophysiological and Experimental Pathology (Y.N., K.S.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; Kyushu University COE Program on Lifestyle-Related Diseases (H.S., K.S.), and Department of Cell Pharmacology (K.K.), Nagoya University, Graduate School of Medicine, Nagoya, Japan.
  • Yasuharu Matsumoto
    From the Department of Cardiovascular Medicine (K.A., H.S., K.M., T.U., K.O., Y.M., T.H.) and Pathophysiological and Experimental Pathology (Y.N., K.S.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; Kyushu University COE Program on Lifestyle-Related Diseases (H.S., K.S.), and Department of Cell Pharmacology (K.K.), Nagoya University, Graduate School of Medicine, Nagoya, Japan.
  • Tsuyoshi Hattori
    From the Department of Cardiovascular Medicine (K.A., H.S., K.M., T.U., K.O., Y.M., T.H.) and Pathophysiological and Experimental Pathology (Y.N., K.S.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; Kyushu University COE Program on Lifestyle-Related Diseases (H.S., K.S.), and Department of Cell Pharmacology (K.K.), Nagoya University, Graduate School of Medicine, Nagoya, Japan.
  • Yutaka Nakashima
    From the Department of Cardiovascular Medicine (K.A., H.S., K.M., T.U., K.O., Y.M., T.H.) and Pathophysiological and Experimental Pathology (Y.N., K.S.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; Kyushu University COE Program on Lifestyle-Related Diseases (H.S., K.S.), and Department of Cell Pharmacology (K.K.), Nagoya University, Graduate School of Medicine, Nagoya, Japan.
  • Kozo Kaibuchi
    From the Department of Cardiovascular Medicine (K.A., H.S., K.M., T.U., K.O., Y.M., T.H.) and Pathophysiological and Experimental Pathology (Y.N., K.S.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; Kyushu University COE Program on Lifestyle-Related Diseases (H.S., K.S.), and Department of Cell Pharmacology (K.K.), Nagoya University, Graduate School of Medicine, Nagoya, Japan.
  • Katsuo Sueishi
    From the Department of Cardiovascular Medicine (K.A., H.S., K.M., T.U., K.O., Y.M., T.H.) and Pathophysiological and Experimental Pathology (Y.N., K.S.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; Kyushu University COE Program on Lifestyle-Related Diseases (H.S., K.S.), and Department of Cell Pharmacology (K.K.), Nagoya University, Graduate School of Medicine, Nagoya, Japan.
  • Akira Takeshit
    From the Department of Cardiovascular Medicine (K.A., H.S., K.M., T.U., K.O., Y.M., T.H.) and Pathophysiological and Experimental Pathology (Y.N., K.S.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; Kyushu University COE Program on Lifestyle-Related Diseases (H.S., K.S.), and Department of Cell Pharmacology (K.K.), Nagoya University, Graduate School of Medicine, Nagoya, Japan.

抄録

<jats:p>Primary pulmonary hypertension is a fatal disease characterized by endothelial dysfunction, hypercontraction and proliferation of vascular smooth muscle cells (VSMCs), and migration of inflammatory cells, for which no satisfactory treatment has yet been developed. We have recently demonstrated that intracellular signaling pathway mediated by Rho-kinase, an effector of the small GTPase Rho, is involved in the pathogenesis of arteriosclerosis. In the present study, we examined whether the Rho-kinase–mediated pathway is also involved in the pathogenesis of fatal pulmonary hypertension in rats. Animals received a subcutaneous injection of monocrotaline, which resulted in the development of severe pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular lesions in 3 weeks associated with subsequent high mortality rate. The long-term blockade of Rho-kinase with fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil after oral administration, markedly improved survival when started concomitantly with monocrotaline and even when started after development of pulmonary hypertension. The fasudil treatment improved pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular lesions with suppression of VSMC proliferation and macrophage infiltration, enhanced VSMC apoptosis, and amelioration of endothelial dysfunction and VSMC hypercontraction. These results indicate that Rho-kinase–mediated pathway is substantially involved in the pathogenesis of pulmonary hypertension, suggesting that the molecule could be a novel therapeutic target for the fatal disorder.</jats:p>

収録刊行物

  • Circulation Research

    Circulation Research 94 (3), 385-393, 2004-02-20

    Ovid Technologies (Wolters Kluwer Health)

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