Activin a and follistatin-like 3 determine the susceptibility of heart to ischemic injury

Yuichi Oshima, Noriyuki Ouchi, Masayuki Shimano, David R. Pimentel, Kyriakos N. Papanicolaou, Kalyani D. Panse, Kunihiro Tsuchida, Enrique Lara-Pezzi, Se Jin Lee, Kenneth Walsh

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Abstract

BACKGROUND-: Transforming growth factor-β family cytokines have diverse actions in the maintenance of cardiac homeostasis. Activin A is a member of this family whose regulation and function in heart are not well understood at a molecular level. Follistatin-like 3 (Fstl3) is an extracellular regulator of activin A protein, and its function in the heart is also unknown. METHODS AND RESULTS-: We analyzed the expression of various transforming growth factor-β superfamily cytokines and their binding partners in mouse heart. Activin βA and Fstl3 were upregulated in models of myocardial injury. Overexpression of activin A with an adenoviral vector (Ad-actβA) or treatment with recombinant activin A protein protected cultured myocytes from hypoxia/reoxygenation-induced apoptosis. Systemic overexpression of activin A in mice by intravenous injection of Ad-actβA protected hearts from ischemia/reperfusion injury. Activin A induced the expression of Bcl-2, and ablation of Bcl-2 by small interfering RNA abrogated its protective action in myocytes. The protective effect of activin A on cultured myocytes was abolished by treatment with Fstl3 or by a pharmacological activin receptor-like kinase inhibitor. Cardiac-specific Fstl3 knockout mice showed significantly smaller infarcts after ischemia/reperfusion injury that was accompanied by reduced apoptosis. CONCLUSIONS-: Activin A and Fstl3 are induced in heart by myocardial stress. Activin A protects myocytes from death, and this activity is antagonized by Fstl3. Thus, the relative expression levels of these factors after injury is a determinant of cell survival in the heart.

Original languageEnglish
Pages (from-to)1606-1615
Number of pages10
JournalCirculation
Volume120
Issue number16
DOIs
Publication statusPublished - 10-2009

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Oshima, Y., Ouchi, N., Shimano, M., Pimentel, D. R., Papanicolaou, K. N., Panse, K. D., Tsuchida, K., Lara-Pezzi, E., Lee, S. J., & Walsh, K. (2009). Activin a and follistatin-like 3 determine the susceptibility of heart to ischemic injury. Circulation, 120(16), 1606-1615. https://doi.org/10.1161/CIRCULATIONAHA.109.872200