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

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

研究成果: Article査読

95 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)280-285
ページ数6
ジャーナルJournal of Cardiovascular Pharmacology
48
6
DOI
出版ステータスPublished - 12-2006
外部発表はい

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

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