title: Targeted deletion of ROCK1 protects the heart against pressure overload by inhibiting reactive fibrosis.
abstract: Ventricular myocyte hypertrophy is an important compensatory growth response to pressure overload. However, pathophysiological cardiac hypertrophy is accompanied by reactive fibrosis and remodeling. The Rho kinase family, consisting of ROCK1 and ROCK2, has been implicated in cardiac hypertrophy and ventricular remodeling. However, these previous studies relied heavily on pharmacological inhibitors,and not on gene deletion. Here we used ROCK1knockout (ROCK1-/-) mice to investigate role of ROCK1 in the development of ventricular remodeling induced by transverse aortic banding. We observed that ROCK1 deletion did not impair compensatory hypertrophic response induced by pressure overload. However, ROCK1-/- mice exhibited reduced perivascular and interstitial fibrosis, which was observed at 3 wk but not at 1 wk after the banding. The reduced fibrosis in the myocardium of ROCK1-/- mice was closely associated with reduced expression of a variety of extracellular matrix (ECM) proteins and fibrogenic cytokines such as TGFbeta2 and connective tissue growth factor. This inhibitory effect of ROCK1 deletion on pathophysiological induction of fibrogenic cytokines was further confirmed in the myocardium of transgenic mice with cardiomyocyte-specific overexpression of Gq. Thus, these results indicate that ROCK1 contributes to the development of cardiac fibrosis and induction of fibrogenic cytokines in cardiomyocytes in response to pathological stimuli.
authors: The Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University, School of Medicine, R4 building, Rm. 370, 1044 West Walnut St., Indianapolis, Indiana 46202-5225, USA.
authors: Ying-Min
authors: YM
authors: Zhang
authors: Jacqueline
authors: J
authors: Bo
authors: George E
authors: GE
authors: Taffet
authors: Jiang
authors: J
authors: Chang
authors: Jianjian
authors: J
authors: Shi
authors: Anilkumar K
authors: AK
authors: Reddy
authors: Lloyd H
authors: LH
authors: Michael
authors: Michael D
authors: MD
authors: Schneider
authors: Mark L
authors: ML
authors: Entman
authors: Robert J
authors: RJ
authors: Schwartz
authors: Lei
authors: L
authors: Wei