Long-term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in mice

Kotaro Abe, Shunsuke Tawara, Keiji Oi, Takatoshi Hizume, Toyokazu Uwatoku, Yoshihiro Fukumoto, Kozo Kaibuchi, Hiroaki Shimokawa

Research output: Contribution to journalArticle

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Abstract

Pulmonary hypertension (PH) is a fatal disease characterized by endothelial dysfunction, hypercontraction and proliferation of vascular smooth muscle cells, and migration of inflammatory cells for which no satisfactory treatment has yet been developed. It has been recently demonstrated that Rho-kinase, an effector of the small GTPase Rho, is involved in the pathogenesis of arteriosclerosis and that long-term inhibition of Rho-kinase markedly ameliorates monocrotaline-induced PH in rats. However, it remains to be examined whether direct inhibition of Rho-kinase also ameliorates PH with a different etiology and whether endothelial nitric oxide synthase (eNOS) is involved in the beneficial effects of Rho-kinase inhibition. This study was designed to address those 2 important issues in a hypoxia-induced PH model using wild-type (WT) and eNOS-deficient (eNOS) mice. Long-term blockade of Rho-kinase with fasudil (100 mg/kg/d) for 3 weeks markedly improved PH and right ventricular hypertrophy in WT mice with a lesser but significant inhibition noted in eNOS mice. Fasudil upregulated eNOS with increased Akt phosphorylation in WT but not in eNOS mice. These results suggest that long-term inhibition of Rho-kinase also ameliorates hypoxia-induced PH in mice, for which eNOS activation may partially be involved.

Original languageEnglish
Pages (from-to)280-285
Number of pages6
JournalJournal of Cardiovascular Pharmacology
Volume48
Issue number6
DOIs
Publication statusPublished - Dec 1 2006

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rho-Associated Kinases
Nitric Oxide Synthase Type III
Pulmonary Hypertension
Monocrotaline
Right Ventricular Hypertrophy
Monomeric GTP-Binding Proteins
Arteriosclerosis
Hypoxia
Vascular Smooth Muscle
Smooth Muscle Myocytes
Cell Movement
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Long-term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in mice. / Abe, Kotaro; Tawara, Shunsuke; Oi, Keiji; Hizume, Takatoshi; Uwatoku, Toyokazu; Fukumoto, Yoshihiro; Kaibuchi, Kozo; Shimokawa, Hiroaki.

In: Journal of Cardiovascular Pharmacology, Vol. 48, No. 6, 01.12.2006, p. 280-285.

Research output: Contribution to journalArticle

Abe, Kotaro ; Tawara, Shunsuke ; Oi, Keiji ; Hizume, Takatoshi ; Uwatoku, Toyokazu ; Fukumoto, Yoshihiro ; Kaibuchi, Kozo ; Shimokawa, Hiroaki. / Long-term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in mice. In: Journal of Cardiovascular Pharmacology. 2006 ; Vol. 48, No. 6. pp. 280-285.
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