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(Circulation. 2009;120:1606-1615.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

Activin A and Follistatin-Like 3 Determine the Susceptibility of Heart to Ischemic Injury

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

From the Molecular Cardiology Unit, Whitaker Cardiovascular Institute (Y.O., N.O., M.S., K.N.P., K.W.), and the Myocardial Biology Unit (D.R.P.), Boston University Medical Campus, Boston, Mass; Imperial College London, Heart Science Centre, Harefield, United Kingdom (K.D.P., E.L.-P.); Division for Therapies Against Intractable Diseases, Institute for Comprehensive Medical Sciences, Fujita Health University, Toyoake, Japan (K.T.); and Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Md (S.L.).

Correspondence to Kenneth Walsh, PhD, Molecular Cardiology Unit/Whitaker Cardiovascular Institute, Boston University Medical Campus, 700 Albany St, W611, Boston, MA 02118. E-mail kxwalsh{at}bu.edu

Received April 9, 2009; accepted August 13, 2009.

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.

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Clinical Summaries
Circulation 2009 120: 1553-1554. [Extract] [Full Text]