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Transforming growth factor-β-mediated CD44/STAT3 signaling contributes to the development of atrial fibrosis and fibrillation

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Abstract

Atrial fibrillation (AF) is associated with atrial fibrosis. Inhibition of atrial fibrosis might be a plausible approach for AF prevention and therapy. This study is designed to evaluate the potential role of CD44, a membrane receptor known to regulate fibrosis, and its related signaling in the pathogenesis of atrial fibrosis and AF. Treatment of cultured rat atrial fibroblasts with transforming growth factor-β (TGF-β, a key mediator of atrial fibrosis) led to a higher expression of hyaluronan (HA), CD44, STAT3, and collagen (a principal marker of fibrosis) than that of ventricular fibroblasts. In vivo, TGF-β transgenic mice and AF patients exhibited a greater expression of HA, CD44, STAT3, and collagen in their atria than wild-type mice and sinus rhythm subjects, respectively. Treating TGF-β transgenic mice with an anti-CD44 blocking antibody resulted in a lower expression of STAT3 and collagen in their atria than those with control IgG antibody. Programmed stimulation triggered less AF episodes in TGF-β transgenic mice treated with anti-CD44 blocking antibody than in those with control IgG. Blocking CD44 signaling with anti-CD44 antibody and mutated CD44 plasmids attenuated TGF-β-induced STAT3 activation and collagen expression in cultured atrial fibroblasts. Deletion and mutational analysis of the collagen promoter along with chromatin immunoprecipitation demonstrated that STAT3 served as a vital transcription factor in collagen expression. TGF-β-mediated HA/CD44/STAT3 pathway plays a crucial role in the development of atrial fibrosis and AF. Blocking CD44-dependent signaling may be a feasible way for AF management.

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Acknowledgements

We thank Mr. Chih-Chun Chen for his technical assistance in confocal microscopy.

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Author notes

  1. Shang-Hung Chang and Yung-Hsin Yeh contribute equally to this work.

Authors and Affiliations

  1. Cardiovascular Division, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Fu-Shin Road No. 5, Kwei-Shan, Taoyuan, 333, Taiwan

    Shang-Hung Chang, Yung-Hsin Yeh, Chi-Tai Kuo & Wei-Jan Chen

  2. Department of Medical Science, Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan

    Jia-Lin Lee

  3. Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

    Yu-Juei Hsu

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  1. Shang-Hung Chang
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Correspondence to Wei-Jan Chen.

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Funding

This work was supported by grants from Chang Gung Research Grant Foundation (CMRPG 3B1691-3, 3D1331-3, 3D1631-3, 3F0991-3, and 3F2281) and from Ministry of Science and Technology, Taiwan (102-2628-B-182-011-MY3, 104-2314-B-182A-135-MY2, and 104-2314-B-182-052-MY3).

Conflict of interest

US patent is issued for the method in treating and/or preventing AF patients with a pharmaceutical composition containing an anti-CD44 neutralizing antibody or an antigen binding portion.

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Chang, SH., Yeh, YH., Lee, JL. et al. Transforming growth factor-β-mediated CD44/STAT3 signaling contributes to the development of atrial fibrosis and fibrillation. Basic Res Cardiol 112, 58 (2017). https://doi.org/10.1007/s00395-017-0647-9

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