Published online before print April 19, 2004, doi: 10.1161/01.CIR.0000127939.16111.58
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(Circulation. 2004;109:2234-2239.)
© 2004 American Heart Association, Inc.
Basic Science Reports |
Long-Term Inhibition of Rho-Kinase Suppresses Left Ventricular Remodeling After Myocardial Infarction in Mice
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.
Correspondence to Hiroaki Shimokawa, MD, PhD, Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan 812-8582. E-mail shimo{at}cardiol.med.kyushu-u.ac.jp
Received September 1, 2003; de novo received November 24, 2003; revision received February 3, 2004; accepted February 5, 2004.
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)-ß2, TGF-ß3, 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.
Key Words: myocardial infarction • heart failure • myocardium • remodeling • signal transduction
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