on April 19, 2004
Published online before print April 19, 2004, doi: 10.1161/01.CIR.0000127939.16111.58
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Submitted on September 1, 2003
From the Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka (T.H., H.S.. M.H., J.H., Y.M., H.T., A.T.); the Kyushu University COE Program on Lifestyle-Related Diseases (H.S.); and the Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya (K.K.), Japan. * To whom correspondence should be addressed. E-mail: shimo{at}cardiol.med.kyushu-u.ac.jp.
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)- 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.
Revised on February 3, 2004
Accepted on February 5, 2004
Long-Term Inhibition of Rho-Kinase Suppresses Left Ventricular Remodeling After Myocardial Infarction in Mice
Tsuyoshi Hattori BS,
2, TGF-3, 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).
Key words: myocardial infarction • heart failure • myocardium • remodeling • signal transduction
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