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 Tsai, Jiin Cherng Yen*, Shiang Suo Huang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

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.

Original languageEnglish
Article number20
JournalBasic Research in Cardiology
Volume114
Issue number3
DOIs
StatePublished - 1 May 2019

Keywords

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

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