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

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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.

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Acknowledgments

This study was supported by the National Science Council of Taiwan (NSC97-2410-H029-037-MY2 and NSC99-2410-H029-059-MY2). This study is also supported in part by Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH100-TD-B-111-004). We also thank Joel A. Newson for his careful editing of the manuscript.

Conflict of interest

The authors state no conflict of interest.

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Authors and Affiliations

  1. School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan, ROC

    Tsung-Jung Ho

  2. Chinese Medicine Department, China Medical University Beigang Hospital, Yunlin County, 65152, Taiwan, ROC

    Tsung-Jung Ho

  3. Graduate Institute of Sports Science, National Taiwan Sport University, Taoyuan, 33301, Taiwan, ROC

    Chi-Chang Huang

  4. Graduate Institute of Basic Medical Science, China Medical University, Taichung, 40402, Taiwan, ROC

    Chih-Yang Huang

  5. Department of Health and Nutrition Biotechnology, Asia University, Taichung, 41354, Taiwan, ROC

    Chih-Yang Huang

  6. Department of Hospitality Management, College of Agriculture, Tunghai University, No.181, Sec. 3, Taichung Port Rd., Situn District, Taichung, 40704, Taiwan, ROC

    Wan-Teng Lin

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  1. Tsung-Jung Ho
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Correspondence to Wan-Teng Lin.

Additional information

Communicated by Keith Phillip George.

T.-J. Ho, C.-C. Huang and C.-Y. Huang contributed equally to this work and appear in alphabetical order.

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Ho, TJ., Huang, CC., Huang, CY. et al. Fasudil, a Rho-kinase inhibitor, protects against excessive endurance exercise training-induced cardiac hypertrophy, apoptosis and fibrosis in rats. Eur J Appl Physiol 112, 2943–2955 (2012). https://doi.org/10.1007/s00421-011-2270-z

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  • DOI: https://doi.org/10.1007/s00421-011-2270-z

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