Long-term inhibition of Rho-kinase ameliorates diastolic heart failure in hypertensive rats

Shigefumi Fukui, Yoshihiro Fukumoto, Jun Suzuki, Kenya Saji, Jun Nawata, Shunsuke Tawara, Tsuyoshi Shinozaki, Yutaka Kagaya, Hiroaki Shimokawa

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Diastolic heart failure (DHF) is a major cardiovascular disorder with poor prognosis; however, its molecular mechanism still remains to be fully elucidated. We have previously demonstrated the important roles of Rho-kinase pathway in the molecular mechanisms of cardiovascular fibrosis/hypertrophy and oxidative stress, but not examined in the development of heart failure. Therefore, we examined in this study whether Rho-kinase pathway is also involved in the pathogenesis of DHF in Dahl salt-sensitive rats, an established animal model of DHF. They were maintained with or without fasudil, a Rho-kinase inhibitor (30 or 100 mg/kg/day, PO) for 10 weeks. Untreated DHF group exhibited overt heart failure associated with diastolic dysfunction but with preserved systolic function, characterized by increased myocardial stiffness, cardiomyocyte hypertrophy, and enhanced cardiac fibrosis and superoxide production. Fasudil treatment significantly ameliorated those DHF-related myocardial changes. Western blot analysis showed that cardiac Rho-kinase activity was significantly increased in the untreated DHF group and was dose-dependently inhibited by fasudil. Importantly, there was a significant correlation between the extent of myocardial stiffness and that of cardiac Rho-kinase activity. These results indicate that Rho-kinase pathway plays an important role in the pathogenesis of DHF and thus could be an important therapeutic target for the disorder.

Original languageEnglish
Pages (from-to)317-326
Number of pages10
JournalJournal of Cardiovascular Pharmacology
Volume51
Issue number3
DOIs
Publication statusPublished - 2008 Mar 1

Keywords

  • Diastolic dysfunction
  • Fibrosis
  • Heart failure
  • Myocardial stiffness
  • Rho-kinase

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Long-term inhibition of Rho-kinase ameliorates diastolic heart failure in hypertensive rats'. Together they form a unique fingerprint.

  • Cite this