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

Background— Transforming growth factor-&bgr; 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-&bgr; superfamily cytokines and their binding partners in mouse heart. Activin &bgr;A and Fstl3 were upregulated in models of myocardial injury. Overexpression of activin A with an adenoviral vector (Ad-act&bgr;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&bgr;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.

[1]  K. Walsh,et al.  Follistatin-like 1, a Secreted Muscle Protein, Promotes Endothelial Cell Function and Revascularization in Ischemic Tissue through a Nitric-oxide Synthase-dependent Mechanism* , 2008, Journal of Biological Chemistry.

[2]  N. Rosenthal,et al.  Expression of follistatin-related genes is altered in heart failure. , 2008, Endocrinology.

[3]  K. Walsh,et al.  Follistatin-Like 1 Is an Akt-Regulated Cardioprotective Factor That Is Secreted by the Heart , 2008, Circulation.

[4]  J. Schneider,et al.  Angiogenic-regulatory network revealed by molecular profiling heart tissue following Akt1 induction in endothelial cells , 2008, Angiogenesis.

[5]  T. Amit,et al.  The neuroprotective effect of Activin A and B: implication for neurodegenerative diseases , 2007, Journal of neurochemistry.

[6]  W. D. Fairlie,et al.  Tumor-induced anorexia and weight loss are mediated by the TGF-β superfamily cytokine MIC-1 , 2007, Nature Medicine.

[7]  S. Engelhardt,et al.  A Secretion Trap Screen in Yeast Identifies Protease Inhibitor 16 as a Novel Antihypertrophic Protein Secreted From the Heart , 2007, Circulation.

[8]  M. Hedger,et al.  Activin A is a critical component of the inflammatory response, and its binding protein, follistatin, reduces mortality in endotoxemia , 2007, Proceedings of the National Academy of Sciences.

[9]  P. Ponikowski,et al.  Prognostic utility of growth differentiation factor-15 in patients with chronic heart failure. , 2007, Journal of the American College of Cardiology.

[10]  S. Kihara,et al.  Adiponectin accumulates in myocardial tissue that has been damaged by ischemia-reperfusion injury via leakage from the vascular compartment. , 2007, Cardiovascular research.

[11]  R. Califf,et al.  Prognostic Value of Growth-Differentiation Factor-15 in Patients With Non–ST-Elevation Acute Coronary Syndrome , 2007, Circulation.

[12]  T. O’Connell,et al.  Isolation and culture of adult mouse cardiac myocytes. , 2007, Methods in molecular biology.

[13]  E. Rosen,et al.  FSTL3 deletion reveals roles for TGF-β family ligands in glucose and fat homeostasis in adults , 2007, Proceedings of the National Academy of Sciences.

[14]  I. Shiojima,et al.  Microarray analysis of Akt1 activation in transgenic mouse hearts reveals transcript expression profiles associated with compensatory hypertrophy and failure. , 2006, Physiological genomics.

[15]  S. Cook,et al.  Myostatin Regulates Cardiomyocyte Growth Through Modulation of Akt Signaling , 2006, Circulation research.

[16]  I. Shiojima,et al.  Vascular Endothelial Growth Factor Blockade Promotes the Transition From Compensatory Cardiac Hypertrophy to Failure in Response to Pressure Overload , 2006, Hypertension.

[17]  H. Drexler,et al.  The Transforming Growth Factor-&bgr; Superfamily Member Growth-Differentiation Factor-15 Protects the Heart From Ischemia/Reperfusion Injury , 2006 .

[18]  T. Hewett,et al.  GDF15/MIC-1 Functions As a Protective and Antihypertrophic Factor Released From the Myocardium in Association With SMAD Protein Activation , 2006, Circulation research.

[19]  H. Drexler,et al.  The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. , 2006, Circulation research.

[20]  D. Phillips,et al.  Follistatin attenuates early liver fibrosis: effects on hepatic stellate cell activation and hepatocyte apoptosis. , 2006, American journal of physiology. Gastrointestinal and liver physiology.

[21]  S. Kihara,et al.  Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2–dependent mechanisms , 2005, Nature Medicine.

[22]  I. Shiojima,et al.  Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. , 2005, The Journal of clinical investigation.

[23]  I. Kawase,et al.  Smad1 Protects Cardiomyocytes From Ischemia-Reperfusion Injury , 2005, Circulation.

[24]  G. Takemura,et al.  Postinfarction Gene Therapy Against Transforming Growth Factor-β Signal Modulates Infarct Tissue Dynamics and Attenuates Left Ventricular Remodeling and Heart Failure , 2005 .

[25]  G. Takemura,et al.  Postinfarction gene therapy against transforming growth factor-beta signal modulates infarct tissue dynamics and attenuates left ventricular remodeling and heart failure. , 2004, Circulation.

[26]  S. Kihara,et al.  Adiponectin-mediated modulation of hypertrophic signals in the heart , 2004, Nature Medicine.

[27]  Michael D. Schneider,et al.  Transgenic Expression of Bcl-2 Modulates Energy Metabolism, Prevents Cytosolic Acidification During Ischemia, and Reduces Ischemia/Reperfusion Injury , 2004, Circulation research.

[28]  G. Christensen,et al.  Elevated Levels of Activin A in Heart Failure: Potential Role in Myocardial Remodeling , 2004, Circulation.

[29]  G. Taffet,et al.  Bcl-2 overexpression corrects mitochondrial defects and ameliorates inherited desmin null cardiomyopathy. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[30]  R. Voutilainen,et al.  Expression of activin/inhibin signaling components in the human adrenal gland and the effects of activins and inhibins on adrenocortical steroidogenesis and apoptosis. , 2003, The Journal of endocrinology.

[31]  J. Massagué,et al.  Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus , 2003, Cell.

[32]  J. Massagué,et al.  Mechanisms of TGF-beta signaling from cell membrane to the nucleus. , 2003, Cell.

[33]  F. Netter,et al.  Supplemental References , 2002, We Came Naked and Barefoot.

[34]  G. Krystal,et al.  Activin/TGF-β induce apoptosis through Smad-dependent expression of the lipid phosphatase SHIP , 2002, Nature Cell Biology.

[35]  T. Zimmers,et al.  Induction of Cachexia in Mice by Systemically Administered Myostatin , 2002, Science.

[36]  T. Doetschman,et al.  TGF-β1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II , 2002 .

[37]  T. Doetschman,et al.  TGF-beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II. , 2002, The Journal of clinical investigation.

[38]  S. Werner,et al.  Impaired wound healing in transgenic mice overexpressing the activin antagonist follistatin in the epidermis , 2001, The EMBO journal.

[39]  Y. Fujio,et al.  Bone Morphogenetic Protein-2 Inhibits Serum Deprivation-induced Apoptosis of Neonatal Cardiac Myocytes through Activation of the Smad1 Pathway* , 2001, The Journal of Biological Chemistry.

[40]  R. Kitsis,et al.  Akt promotes survival of cardiomyocytes in vitro and protects against ischemia-reperfusion injury in mouse heart. , 2000, Circulation.

[41]  R. Balling,et al.  Overexpression of activin A in the skin of transgenic mice reveals new activities of activin in epidermal morphogenesis, dermal fibrosis and wound repair , 1999, The EMBO journal.

[42]  P. Gluckman,et al.  Administration of recombinant human activin-A has powerful neurotrophic effects on select striatal phenotypes in the quinolinic acid lesion model of Huntington's disease , 1999, Neuroscience.

[43]  P. Gluckman,et al.  Expression of the activin axis and neuronal rescue effects of recombinant activin A following hypoxic-ischemic brain injury in the infant rat 1 Published on the World Wide Web on 8 June 1999. 1 , 1999, Brain Research.

[44]  K. Matthews,et al.  Myostatin, a transforming growth factor‐β superfamily member, is expressed in heart muscle and is upregulated in cardiomyocytes after infarct , 1999, Journal of cellular physiology.

[45]  R. Jaenisch,et al.  Functional analysis of activins during mammalian development , 1995, Nature.

[46]  A. Bradley,et al.  Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[47]  W. Fischer,et al.  Activin is a nerve cell survival molecule , 1990, Nature.

[48]  H. Shibai,et al.  Erythroid differentiation factor is encoded by the same mRNA as that of the inhibin beta A chain. , 1988, Proceedings of the National Academy of Sciences of the United States of America.