ha-1100 and Ventricular-Dysfunction--Left

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.. Mice underwent ligation of the left coronary artery and were treated with a Rho-kinase inhibitor, fasudil (100 mg x kg(-1) x 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)-beta2, TGF-beta3, 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).. 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.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; DNA-Binding Proteins; Drug Administration Schedule; Enzyme Inhibitors; Fibrosis; Gene Expression Regulation; Hypertrophy, Left Ventricular; Intramolecular Oxidoreductases; Macrophage Migration-Inhibitory Factors; Male; Mice; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Organ Size; Phosphorylation; Protein Processing, Post-Translational; Transcription Factors; Transforming Growth Factor beta; Transforming Growth Factor beta2; Transforming Growth Factor beta3; Ultrasonography; Ventricular Dysfunction, Left; Ventricular Remodeling