title: Activin A and follistatin-like 3 determine the susceptibility of heart to ischemic injury.
abstract: BACKGROUND
  Transforming growth factor-beta 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.
  
  
  RESULTS
  We analyzed the expression of various transforming growth factor-beta superfamily cytokines and their binding partners in mouse heart. Activin betaA and Fstl3 were upregulated in models of myocardial injury. Overexpression of activin A with an adenoviral vector (Ad-actbetaA) 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-actbetaA 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.
authors.affiliation: Molecular Cardiology Unit, Whitaker Cardiovascular Institute, Boston University Medical Campus, Boston, Mass 02118, USA.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oshima
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ouchi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimano
authors.forename: David R
authors.initials: DR
authors.lastname: Pimentel
authors.forename: Kyriakos N
authors.initials: KN
authors.lastname: Papanicolaou
authors.forename: Kalyani D
authors.initials: KD
authors.lastname: Panse
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Tsuchida
authors.forename: Enrique
authors.initials: E
authors.lastname: Lara-Pezzi
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
mesh_terms: D029404:Activin Receptors / Q000494:pharmacology; D028341:Activins / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia; D002470:Cell Survival; D002478:Cells, Cultured; D003331:Coronary Vessels; D004198:Disease Susceptibility; D038702:Follistatin-Related Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D018014:Gene Transfer Techniques; D006352:Heart Ventricles; D007275:Injections, Intravenous; D008026:Ligation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000378:metabolism; D017202:Myocardial Ischemia / Q000209:etiology*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage; D015854:Up-Regulation
chemical_list: D038702:Follistatin-Related Proteins; D011994:Recombinant Proteins; C422405:activin A; D028341:Activins; D029404:Activin Receptors; D010100:Oxygen