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Exogenous GDF11 attenuates non-canonical TGF-β signaling to protect the heart from acute myocardial ischemia–reperfusion injury

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Abstract

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor beta 1 (TGF-β1) superfamily that reverses age-related cardiac hypertrophy, improves muscle regeneration and angiogenesis, and maintains progenitor cells in injured tissue. Recently, targeted myocardial delivery of the GDF11 gene in aged mice was found to reduce heart failure and enhance the proliferation of cardiac progenitor cells after myocardial ischemia–reperfusion (I–R). No investigations have as yet explored the cardioprotective effect of exogenous recombinant GDF11 in acute I–R injury, despite the convenience of its clinical application. We sought to determine whether exogenous recombinant GDF11 protects against acute myocardial I–R injury and investigate the underlying mechanism in Sprague–Dawley rats. We found that GDF11 reduced arrhythmia severity and successfully attenuated myocardial infarction; GDF11 also increased cardiac function after I–R, enhanced HO-1 expression and decreased oxidative damage. GDF11 activated the canonical TGF-β signaling pathway and inactivated the non-canonical pathways, ERK and JNK signaling pathways. Moreover, administration of GDF11 prior to reperfusion protected the heart from reperfusion damage. Notably, pretreatment with the activin-binding protein, follistatin (FST), inhibited the cardioprotective effects of GDF11 by blocking its activation of Smad2/3 signaling and its inactivation of detrimental TGF-β signaling. Our data suggest that exogenous GDF11 has cardioprotective effects and may have morphologic and functional recovery in the early stage of myocardial I–R injury. GDF11 may be an innovative therapeutic approach for reducing myocardial I–R injury.

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Acknowledgements

Cryostat preparation for frozen sections and upright fluorescence microscopy investigations were performed in the Instrument Center of Chung Shan Medical University, which is supported by Chung Shan Medical University and National Science Council, Ministry of Education, Taichung, Taiwan.

Funding

This work was supported by research grants from Taiwan’s Ministry of Science and Technology (MOST) 106-2320-B-040-005 and MOST 106-2314-B-350-003 given to S-SH and S-KT.

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Authors and Affiliations

  1. Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, No. 155, Sec. 2, Lih-Nong Street, Taipei, 11221, Taiwan

    Hsing-Hui Su & Jiin-Cherng Yen

  2. Department of Physiology, Chung Shan Medical University and Chung Shan Medical University Hospital, Taichung, Taiwan

    Jiuan-Miaw Liao

  3. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan

    Yi-Hsin Wang, Jing-Yang Huang & Shiang-Suo Huang

  4. Department of Parasitology, Chung Shan Medical University, Taichung, Taiwan

    Ke-Min Chen

  5. Institute of Biochemistry, Microbiology and Immunology, Medical College of Chung Shan Medical University, Taichung, Taiwan

    Chia-Wei Lin

  6. Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan

    I-Hui Lee

  7. Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan

    I-Hui Lee

  8. Department of Pathology, Chung Shan Medical University, Taichung, Taiwan

    Yi-Ju Li

  9. Department of Pathology, Chung Shan Medical University Hospital, Taichung, Taiwan

    Yi-Ju Li

  10. Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan

    Jing-Yang Huang

  11. Cheng-Hsin General Hospital, No 45, Cheng Hsin St, Beitou, Taipei, Taiwan

    Shen Kou Tsai

  12. Department of Pharmacology, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Rd., Taichung, 402, Taiwan

    Shiang-Suo Huang

  13. Department of Pharmacy, Chung Shan Medical University Hospital, No. 110, Sec. 1, Jianguo N. Rd., Taichung, 402, Taiwan

    Shiang-Suo Huang

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  1. Hsing-Hui Su
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Su, HH., Liao, JM., Wang, YH. et al. Exogenous GDF11 attenuates non-canonical TGF-β signaling to protect the heart from acute myocardial ischemia–reperfusion injury. Basic Res Cardiol 114, 20 (2019). https://doi.org/10.1007/s00395-019-0728-z

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