Fasudil hydrochloride hydrate, a Rho-kinase inhibitor, suppresses isoproterenol-induced heart failure in rats via JNK and ERK1/2 pathways

• Published in: Journal of cellular biochemistry 2011-07, Vol.112 (7), p.1920-1929
• Main Authors: Wang, Na, Guan, Peng, Zhang, Jian-Ping, Li, Ya-Qing, Chang, Yan-Zhong, Shi, Zhen-Hua, Wang, Feng-Yun, Chu, Li
• Format: Article
• Language: English
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology; Animals; CASP8 and FADD-Like Apoptosis Regulating Protein - genetics; CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism; Enzyme Activation; FASUDIL; Gene Expression; Heart - drug effects; Heart - physiopathology; HEART FAILURE; Heart Failure - chemically induced; Heart Failure - prevention & control; Hemodynamics - drug effects; ISOPROTERENOL; Male; MAP Kinase Signaling System - drug effects; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Mitogen-Activated Protein Kinase 8 - genetics; Mitogen-Activated Protein Kinase 8 - metabolism; Myocardium - pathology; Organ Size - drug effects; Rats; Rats, Sprague-Dawley; rho-Associated Kinases - antagonists & inhibitors; rho-Associated Kinases - metabolism; RHO-KINASE
• ISSN: 0730-2312; 1097-4644
• 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‐FLIPL 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. J. Cell. Biochem. 112: 1920–1929, 2011. © 2011 Wiley‐Liss, Inc.