Department of Pharmacology, School of Basic Medicine, Heibei Medical University, Shijiazhuang 050091, Hebei, China.
J Cell Biochem. 2011 Jul;112(7):1920-9. doi: 10.1002/jcb.23112.
The Rho-kinase (ROCK) plays an important role in the pathogenesis of heart injury. Recent cellular and molecular biology studies indicated a pivotal role of the RhoA/ROCK cascade in many aspects of cardiovascular function such as heart failure, cardiac hypertrophy, and ventricular remodeling following myocardial infarction. However, the signal transduction of RhoA/ROCK and its down-stream signaling pathways remains elusive, and the mechanism of ROCK-mediated isoproterenol (ISO)-induced heart failure is still not thoroughly understood. In the present study, we investigated the effect of the ROCK inhibitor, fasudil hydrochloride hydrate, on ISO-induced heart failure and the potential relationship of RhoA/ROCK to the extracellular signal-regulated kinases (ERK) and the c-jun NH 2-terminal kinase (JNK) pathways. Male Sprague-Dawley (SD) rats, maintained on a normal diet, were randomly divided into four groups given control, ISO alone, ISO with low-dose fasudil, or ISO with high-dose fasudil treatments. Fasudil effectively inhibited ISO-induced heart failure, as evaluated by biometric, hemodynamic, and histological examinations. Consistently, ISO-induced ROCK-1 mRNA expression and myosin phosphatase target subunit-1 (MYPT-1) phosphorylation were markedly suppressed by fasudil. In addition, fasudil significantly decreased ISO-induced JNK activation, ERK translocation to the nucleus and subsequent c-fos, c-jun expression and upregulated c-FLIP(L) expression. Taken together, these results indicate that the RhoA/ROCK pathway is essential for ISO induced heart failure, which can be effectively suppressed by fasudil.
Rho 激酶（ROCK）在心脏损伤的发病机制中起重要作用。最近的细胞和分子生物学研究表明，RhoA/ROCK 级联在心力衰竭、心肌梗死后的心脏肥大和心室重构等许多心血管功能方面起着关键作用。然而，RhoA/ROCK 的信号转导及其下游信号通路仍不清楚，ROCK 介导的异丙肾上腺素（ISO）诱导的心力衰竭的机制仍未完全阐明。在本研究中，我们研究了 ROCK 抑制剂盐酸法舒地尔对 ISO 诱导的心力衰竭的影响，以及 RhoA/ROCK 与细胞外信号调节激酶（ERK）和 c-jun NH2 末端激酶（JNK）途径的潜在关系。雄性 Sprague-Dawley（SD）大鼠在正常饮食下饲养，随机分为四组，分别给予对照、ISO 单独处理、ISO 与低剂量法舒地尔或 ISO 与高剂量法舒地尔处理。法舒地尔有效抑制了生物计量学、血液动力学和组织学检查评估的 ISO 诱导的心力衰竭。一致地，法舒地尔明显抑制了 ISO 诱导的 ROCK-1 mRNA 表达和肌球蛋白磷酸酶靶亚单位-1（MYPT-1）磷酸化。此外，法舒地尔显著降低了 ISO 诱导的 JNK 激活、ERK 向核内转移以及随后的 c-fos、c-jun 表达，并上调了 c-FLIP（L）表达。总之，这些结果表明，RhoA/ROCK 途径对于 ISO 诱导的心力衰竭是必不可少的，法舒地尔可以有效地抑制其发生。
