Activin A and Follistatin-Like 3 Determine the Susceptibility of Heart to Ischemic Injury | |
Article | |
关键词: GROWTH-DIFFERENTIATION FACTOR-15; BETA SUPERFAMILY MEMBER; REPERFUSION INJURY; ISCHEMIA/REPERFUSION INJURY; CARDIOMYOCYTE GROWTH; CARDIAC-HYPERTROPHY; FAILURE; EXPRESSION; ACTIVATION; APOPTOSIS; | |
DOI : 10.1161/CIRCULATIONAHA.109.872200 | |
来源: SCIE |
【 摘 要 】
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 beta A and Fstl3 were upregulated in models of myocardial injury. Overexpression of activin A with an adenoviral vector (Ad-act beta A) 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-act beta A 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. (Circulation. 2009; 120: 1606-1615.)
【 授权许可】
Free