Inhibition of Rho-kinase ameliorates myocardial remodeling and fibrosis in pressure overload and myocardial infarction: Role of TGF-β1–TAK1

Apr 3, 2012Toxicology letters

Blocking Rho-kinase improves heart tissue changes and scarring after high blood pressure and heart attack through TGF-β1-TAK1

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Abstract

Fasudil treatment significantly suppressed left ventricular cavity dilatation and dysfunction in myocardial infarction mice compared to untreated controls (P<0.05).

Inhibition of Rho-kinase is linked to reduced interstitial fibrosis in both pressure overload and myocardial infarction models (P<0.05).
Fasudil treatment was associated with changes in specific profibrotic gene expression.
The TGF-β1-TAK1 pathway may play a role in the myocardial remodeling process following pressure overload and ischemia.
No significant differences were observed between the TAC group and the fasudil-treated TAC group regarding cardiac outcomes.

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Inhibition of Rho-kinase displays vasodilation property although its effect on cardiac remodeling in heart against pressure overload and ischemia has not been fully elucidated. The present study was designed to examine the effect of fasudil, a Rho-kinase (ROCK) inhibitor, on myocardial remodeling and underlying mechanisms in pressure overload and myocardial infarction (MI) mice. Pressure overload was produced by constriction of the transverse aorta (TAC) for 3 weeks. Left ventricular (LV) geometry, cardiac hypertrophy, fibrosis, and remodeling were evaluated by transthoracic echocardiography and cardiac histology. Expressions of the hypertrophic and profibrotic markers were analyzed in TAC and MI mice with or without fasudil treatment. LV cavity dilatation and dysfunction evaluated by echocardiography were significantly suppressed in the fasudil-treated MI group compared with the MI group (P<0.05); however, there were no significant difference between the TAC group and the fasudil-treated TAC group. Inhibition of ROCK exhibited reduced interstitial fibrosis, which was observed both in TAC and MI mice (P<0.05). The beneficial effects of fasudil were closely associated with the change of the specific profibrotic gene expression and TGF-β1-TAK1 pathway. Taken together, these results indicate that Rho-kinase is substantially involved in the myocardial remodeling after TAC and MI associated with upregulation of profibrotic gene expression and TGF-β1-TAK1 pathway; further suggest the protective effect of fasudil on heart against pathological stimuli by inhibiting reactive fibrosis.

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Inhibition of Rho-kinase ameliorates myocardial remodeling and fibrosis in pressure overload and myocardial infarction: Role of TGF-β1–TAK1

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