Zhang Ying-Min, Bo Jacqueline, Taffet George E, Chang Jiang, Shi Jianjian, Reddy Anilkumar K, Michael Lloyd H, Schneider Michael D, Entman Mark L, Schwartz Robert J, Wei Lei
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.
FASEB J. 2006 May;20(7):916-25. doi: 10.1096/fj.05-5129com.
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.
心室肌细胞肥大是对压力超负荷的一种重要的代偿性生长反应。然而，病理性心脏肥大伴有反应性纤维化和重塑。由ROCK1和ROCK2组成的Rho激酶家族与心脏肥大和心室重塑有关。然而，这些先前的研究严重依赖于药理学抑制剂，而非基因缺失。在这里，我们使用ROCK1基因敲除（ROCK1-/-）小鼠来研究ROCK1在横断主动脉缩窄诱导的心室重塑发展中的作用。我们观察到，ROCK1基因缺失并不损害压力超负荷诱导的代偿性肥大反应。然而，ROCK1-/-小鼠的血管周围和间质纤维化减少，这在缩窄后3周观察到，但在1周时未观察到。ROCK1-/-小鼠心肌纤维化的减少与多种细胞外基质（ECM）蛋白以及纤维化细胞因子如TGFβ2和结缔组织生长因子的表达降低密切相关。ROCK1基因缺失对纤维化细胞因子病理诱导的这种抑制作用在心肌细胞特异性过表达Gq的转基因小鼠心肌中得到进一步证实。因此，这些结果表明，ROCK1在病理性刺激下促进心脏纤维化的发展并诱导心肌细胞中纤维化细胞因子的产生。
