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

Abstract

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.

• Authors: Tsung-Jung Ho, Chi-Chang Huang, Chih-Yang Huang, Wan-Teng Lin
• Journal: European journal of applied physiology (Eur J Appl Physiol) Vol. 112 Issue 8 Pg. 2943-55 (Aug 2012) ISSN: 1439-6327 [Electronic] Germany
• PMID: 22160250 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• Biomarkers
• Protein Kinase Inhibitors
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
• rho-Associated Kinases
• fasudil

Topics

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (analogs & derivatives, pharmacology)
• Animals
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Biomarkers (metabolism)
• Cardiomegaly (enzymology, etiology, pathology, prevention & control)
• Fibrosis
• Male
• Myocardium (enzymology, pathology)
• Physical Endurance
• Protein Kinase Inhibitors (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Time Factors
• Ventricular Remodeling (drug effects)
• rho-Associated Kinases (antagonists & inhibitors, metabolism)