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Fasudil, a Rho-kinase inhibitor, protects against excessive endurance exercise training-induced cardiac hypertrophy, apoptosis and fibrosis in rats.

Authors: Ho, TJ  Huang, CC  Huang, CY  Lin, WT 
Citation: Ho TJ, etal., Eur J Appl Physiol. 2012 Aug;112(8):2943-55. doi: 10.1007/s00421-011-2270-z. Epub 2011 Dec 9.
Pubmed: (View Article at PubMed) PMID:22160250
DOI: Full-text: DOI:10.1007/s00421-011-2270-z

Excessive endurance exercise training (EEET) is accompanied by cardiac remodeling, changes in ventricular function and increased heart failure risk. Fasudil, a potent Rho-kinase inhibitor, has been demonstrated to blunt cardiomyocyte hypertrophy, cardiac remodeling, and heart failure progression in pre-clinical trials and has been approved for clinical use in Japan. We examined the in vivo bioefficacy of fasudil against EEET-induced cardiac remodeling and the underlying molecular mechanisms. Male Sprague-Dawley rats were randomly divided into three groups: sedentary control (SC), EEET, and EEET with fasudil treatment (EEET-F). Rats in EEET and EEET-F groups ran on a motorized treadmill for 12 weeks. The results revealed that EEET increased myocardial hypertrophy (LV weight/tibial length), myocyte cross-sectional area, hypertrophy-related pathways (IL6/STAT3-MEK5-ERK5, calcineurin-NFATc3, p38 and JNK MAPK), hypertrophic markers (ANP/BNP), pro-apoptotic molecules (cytochrome C, cleaved caspase-3 and PARP), and fibrosis-related pathways (FGF-2-ERK1/2) and fibrosis markers (uPA, MMP-9 and -2). These pathways were then expressed lower in the EEET-F group when compared with the EEET group. The cardiac hypertrophic level, apoptotic pathway and fibrosis signaling were further inhibited in the fasudil-treated group. We systematically investigated the possible signaling pathways leading to EEET-induced cardiac hypertrophy, apoptosis and fibrosis. We also provide evidence for the novel function of fasudil in suppressing EEET-induced cardiac remodeling and impairment by multiple mechanisms, which suggests that the RhoA signaling pathway contributes to EEET-induced cardiac remodeling and dysfunction.

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CRRD Object Information
CRRD ID: 7241558
Created: 2013-03-11
Species: All species
Last Modified: 2013-03-11
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.