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

  • Hsing-Hui Su
  • Jiuan-Miaw Liao
  • Yi-Hsin Wang
  • Ke-Min Chen
  • Chia-Wei Lin
  • I-Hui Lee
  • Yi-Ju Li
  • Jing-Yang Huang
  • Shen Kou TsaiEmail author
  • Jiin-Cherng YenEmail author
  • Shiang-Suo HuangEmail author
Original Contribution


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.


Growth differentiation factor 11 Transforming growth factor beta 1 Myocardial ischemia–reperfusion Smad2/3 TGF-β non-canonical pathway 



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.


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.

Compliance with ethical standards

Conflicts of interest

All authors declare that they have no conflicts of interest.

Supplementary material

395_2019_728_MOESM1_ESM.docx (625 kb)
Supplementary material 1 (DOCX 624 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department and Institute of Pharmacology, School of MedicineNational Yang-Ming UniversityTaipeiTaiwan
  2. 2.Department of PhysiologyChung Shan Medical University and Chung Shan Medical University HospitalTaichungTaiwan
  3. 3.Institute of MedicineChung Shan Medical UniversityTaichungTaiwan
  4. 4.Department of ParasitologyChung Shan Medical UniversityTaichungTaiwan
  5. 5.Institute of Biochemistry, Microbiology and ImmunologyMedical College of Chung Shan Medical UniversityTaichungTaiwan
  6. 6.Department of NeurologyTaipei Veterans General HospitalTaipeiTaiwan
  7. 7.Institute of Brain ScienceNational Yang-Ming UniversityTaipeiTaiwan
  8. 8.Department of PathologyChung Shan Medical UniversityTaichungTaiwan
  9. 9.Department of PathologyChung Shan Medical University HospitalTaichungTaiwan
  10. 10.Department of Medical ResearchChung Shan Medical University HospitalTaichungTaiwan
  11. 11.Cheng-Hsin General HospitalTaipeiTaiwan
  12. 12.Department of PharmacologyChung Shan Medical UniversityTaichungTaiwan
  13. 13.Department of PharmacyChung Shan Medical University HospitalTaichungTaiwan

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