Long-Term Inhibition of Rho-Kinase Suppresses Left Ventricular Remodeling after Myocardial Infarction in Mice

Tsuyoshi Hattori, Hiroaki Shimokawa, Midoriko Higashi, Junko Hiroki, Yasushi Mukai, Hiroyuki Tsutsui, Kozo Kaibuchi, Akira Takeshita

研究成果: Article査読

178 被引用数 (Scopus)

抄録

Background-Rho-kinase has been implicated as an important regulator of inflammatory responses mediated by cytokines and chemokines. Because proinflammatory cytokines play a critical role in left ventricular (LV) remodeling after myocardial infarction (MI), we examined whether long-term blockade of Rho-kinase suppresses LV remodeling in a mouse model of MI in vivo. Methods and Results-Mice underwent ligation of the left coronary artery and were treated with a Rho-kinase inhibitor, fasudil (100 mg · kg -1 · d-1 in tap water), for 4 weeks, starting 1 day after the surgery. At 4 weeks, LV infarct size was histologically comparable between the 2 groups. LV cavity dilatation and dysfunction evaluated by echocardiography were significantly suppressed in the fasudil group (P<0.05, n= 15 to 28). The beneficial effects of fasudil were accompanied by suppression of cardiomyocyte hypertrophy and interstitial fibrosis (both P<0.01, n=6). The expression of inflammatory cytokines, including transforming growth factor (TGF)-β2, TGF-β3, and macrophage migration inhibitory factor, was upregulated in the noninfarcted LV in the control group and was significantly suppressed in the fasudil group (both P<0.05, n= 10 to 11). Rho-kinase activity as evaluated by the extent of phosphorylation of the ERM family, a substrate of Rho-kinase, was significantly increased in the noninfarcted LV in the control group and was significantly suppressed in the fasudil group (P<0.05, n=5). Conclusions-These results indicate that Rho-kinase is substantially involved in the pathogenesis of LV remodeling after MI associated with upregulation of proinflammatory cytokines, suggesting a therapeutic importance of the molecule for the prevention of post-MI heart failure.

本文言語English
ページ(範囲)2234-2239
ページ数6
ジャーナルCirculation
109
18
DOI
出版ステータスPublished - 2004 5 11

ASJC Scopus subject areas

  • 循環器および心血管医学
  • 生理学(医学)

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