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

Kohtaro Abe, Hiroaki Shimokawa, Keiko Morikawa, Toyokazu Uwatoku, Keiji Oi, Yasuharu Matsumoto, Tsuyoshi Hattori, Yutaka Nakashima, Kozo Kaibuchi, Katsuo Sueishi, Akira Takeshita

Research output: Contribution to journalArticle

331 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)385-393
Number of pages9
JournalCirculation research
Volume94
Issue number3
DOIs
Publication statusPublished - Feb 20 2004

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Monocrotaline
rho-Associated Kinases
Pulmonary Hypertension
Vascular Smooth Muscle
Smooth Muscle Myocytes
Right Ventricular Hypertrophy
Blood Vessels
Therapeutics
Lung
Monomeric GTP-Binding Proteins
Arteriosclerosis
Subcutaneous Injections
Cell Movement
Oral Administration
Macrophages
Cell Proliferation
Apoptosis
Mortality

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Long-Term Treatment with a Rho-Kinase Inhibitor Improves Monocrotaline-Induced Fatal Pulmonary Hypertension in Rats. / Abe, Kohtaro; Shimokawa, Hiroaki; Morikawa, Keiko; Uwatoku, Toyokazu; Oi, Keiji; Matsumoto, Yasuharu; Hattori, Tsuyoshi; Nakashima, Yutaka; Kaibuchi, Kozo; Sueishi, Katsuo; Takeshita, Akira.

In: Circulation research, Vol. 94, No. 3, 20.02.2004, p. 385-393.

Research output: Contribution to journalArticle

Abe, K, Shimokawa, H, Morikawa, K, Uwatoku, T, Oi, K, Matsumoto, Y, Hattori, T, Nakashima, Y, Kaibuchi, K, Sueishi, K & Takeshita, A 2004, 'Long-Term Treatment with a Rho-Kinase Inhibitor Improves Monocrotaline-Induced Fatal Pulmonary Hypertension in Rats', Circulation research, vol. 94, no. 3, pp. 385-393. https://doi.org/10.1161/01.RES.0000111804.34509.94
Abe, Kohtaro ; Shimokawa, Hiroaki ; Morikawa, Keiko ; Uwatoku, Toyokazu ; Oi, Keiji ; Matsumoto, Yasuharu ; Hattori, Tsuyoshi ; Nakashima, Yutaka ; Kaibuchi, Kozo ; Sueishi, Katsuo ; Takeshita, Akira. / Long-Term Treatment with a Rho-Kinase Inhibitor Improves Monocrotaline-Induced Fatal Pulmonary Hypertension in Rats. In: Circulation research. 2004 ; Vol. 94, No. 3. pp. 385-393.
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