Targeted deletion of ROCK1 protects the heart against pressure overload by inhibiting reactive fibrosis

Ying Min Zhang, Jacqueline Bo, George E. Taffet, Jiang Chang, Jianjian Shi, Anilkumar K. Reddy, Lloyd H. Michael, Michael D. Schneider, Mark L. Entman, Robert J. Schwartz, Lei Wei

Research output: Contribution to journalArticle

152 Scopus citations

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 ROCK1 knockout (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 TGFβ2 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 Gαq. 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.

Original languageEnglish (US)
Pages (from-to)916-925
Number of pages10
JournalFASEB Journal
Volume20
Issue number7
DOIs
StatePublished - May 1 2006

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Keywords

  • Fibrogenic cytokines
  • Fibrosis
  • Hypertrophy
  • Pressure overload
  • Rho kinase

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Zhang, Y. M., Bo, J., Taffet, G. E., Chang, J., Shi, J., Reddy, A. K., Michael, L. H., Schneider, M. D., Entman, M. L., Schwartz, R. J., & Wei, L. (2006). Targeted deletion of ROCK1 protects the heart against pressure overload by inhibiting reactive fibrosis. FASEB Journal, 20(7), 916-925. https://doi.org/10.1096/fj.05-5129com