title: 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.affiliation: School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan, ROC.
authors.forename: Tsung-Jung
authors.initials: TJ
authors.lastname: Ho
authors.forename: Chi-Chang
authors.initials: CC
authors.lastname: Huang
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
authors.forename: Wan-Teng
authors.initials: WT
authors.lastname: Lin
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D006332:Cardiomegaly / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D005355:Fibrosis; D008297:Male; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010807:Physical Endurance; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D020257:Ventricular Remodeling / Q000187:drug effects; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil