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  • Title: Activin A and follistatin-like 3 determine the susceptibility of heart to ischemic injury.
    Author: Oshima Y, Ouchi N, Shimano M, Pimentel DR, Papanicolaou KN, Panse KD, Tsuchida K, Lara-Pezzi E, Lee SJ, Walsh K.
    Journal: Circulation; 2009 Oct 20; 120(16):1606-15. PubMed ID: 19805648.
    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. METHODS AND 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.
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