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首页> 外文期刊>Therapeutic advances in cardiovascular disease. >Mechanisms of favorable effects of Rho kinase inhibition on myocardial remodeling and systolic function after experimental myocardial infarction in the rat
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Mechanisms of favorable effects of Rho kinase inhibition on myocardial remodeling and systolic function after experimental myocardial infarction in the rat

机译：Rho激酶抑制作用对大鼠实验性心肌梗死后心肌重构和收缩功能的有利机制

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The objective of this study was to determine the molecular mechanisms by which cardiac Rho-associated coiled-coil containing protein kinase (ROCK) activation after myocardial infarction (MI) does intervene in cardiac systolic function decline and remodeling. Simultaneous measurement of different cardiac ROCK target proteins levels, in vivo left ventricular (LV) systolic function, myocardial fibrosis and hypertrophy in rats with MI under ROCK inhibition with fasudil. Seven days after MI, the ventricular mass increased significantly by 5.6% in the MI group and was reduced with fasudil. LV systolic dysfunction improved significantly with fasudil whereas cardiac ROCK activation was reduced to sham levels. The ROCK inhibitor also reduced increased cardiac levels of both ROCK1 and ROCK2 isoforms, cardiomyocyte ROCK2 fluorescence levels and β-myosin heavy chain (MHC) levels in addition to myocardial collagen volume fraction decline. Compared with sham rats, troponin phosphorylation levels after MI were similar and ROCK inhibition reduced them. MI significantly increased phosphorylation levels of extracellular-signal-regulated kinase (ERK) 42 and ERK 44 by twofold and 63%, respectively, whereas in the fasudil-treated MI group these levels were similar to those in the sham group. MI significantly increased phosphorylated levels of the transcription factor GATA-4 and the ROCK inhibitor normalized them. LV systolic dysfunction after MI was strongly associated with cardiac ROCK activation and subsequent phosphorylation of ROCK target proteins that promote ventricular remodeling such as β-MHC and the ERK/GATA-4 pathway. ROCK inhibition with fasudil significantly improved systolic function, diminished myocardial fibrosis and normalized β-MHC and ERK/GATA-4 phosphorylation levels.
机译：这项研究的目的是确定分子机制，通过这种分子机制，心肌梗死（MI）后心脏Rho相关的包含蛋白激酶（ROCK）的卷曲螺旋活化确实干预了心脏收缩功能的下降和重塑。同时测定法舒地尔在ROCK抑制下的MI大鼠心脏ROCK靶蛋白水平，体内左心室（LV）收缩功能，心肌纤维化和肥大的不同水平。心肌梗死后7天，心肌梗死组的心室质量明显增加了5.6％，而法舒地尔则减少了。法舒地尔可显着改善左室收缩功能障碍，而心脏ROCK激活可降低至假水平。除了心肌胶原蛋白的体积分数下降外，ROCK抑制剂还降低了ROCK1和ROCK2亚型的心脏水平，心肌细胞ROCK2荧光水平和β-肌球蛋白重链（MHC）水平。与假手术大鼠相比，心肌梗死后肌钙蛋白的磷酸化水平相似，而ROCK抑制使肌钙蛋白磷酸化。 MI显着使细胞外信号调节激酶（ERK）42和ERK 44的磷酸化水平分别增加了两倍和63％，而在接受法舒地尔治疗的MI组中，这些水平与假手术组中的水平相似。 MI显着增加了转录因子GATA-4的磷酸化水平，而ROCK抑制剂使它们标准化。 MI后的LV收缩功能异常与心脏ROCK激活以及随后促进心室重构的ROCK目标蛋白（例如β-MHC和ERK / GATA-4途径）的磷酸化密切相关。法舒地尔对ROCK的抑制作用可显着改善收缩功能，减少心肌纤维化，并使β-MHC和ERK / GATA-4磷酸化水平正常化。

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