In Cardiomyocyte Hypoxia, Insulin-Like Growth Factor-I-Induced Antiapoptotic Signaling Requires Phosphatidylinositol-3-OH-Kinase-Dependent and Mitogen-Activated Protein Kinase-Dependent Activation of the Transcription Factor cAMP Response Element-Binding Protein

Background—A variety of pathologic stimuli lead to apoptosis of cardiomyocytes. Survival factors like insulin-like growth factor-I (IGF-I) exert anti-apoptotic effects in the heart. Yet the underlying signaling pathways are poorly understood. Methods and Results—In a model of hypoxia-induced apoptosis of cultured neonatal cardiomyocytes, IGF-I prevented cell death in a dose-dependent manner. Antiapoptotic signals induced by IGF-I are mediated by more than one signaling pathway, because pharmacological inhibition of the phosphatidylinositol-3-OH-kinase (PI3K) or the mitogen-activated protein kinase kinase (MEK1) signaling pathway both antagonize the protective effect of IGF-I in an additive manner. IGF-I-stimulation was followed by a PI3K-dependent phosphorylation of AKT and BAD and an MEK1-dependent phosphorylation of extracellular signal-regulated kinase (ERK) 1 and ERK2. IGF-I also induced phosphorylation of cAMP response element-binding protein (CREB) in a PI3K- and MEK1-dependent manner. Ectopic overexpression of a dominant-negative mutant of CREB abolished the antiapoptotic effect of IGF-I. Protein levels of the antiapoptotic factor bcl-2 increased after longer periods of IGF-I-stimulation, which could be reversed by pharmacological inhibition of PI3K as well as MEK1 and also by overexpression of dominant-negative CREB. Conclusions—In summary, our data demonstrate that in cardiomyocytes, the antiapoptotic effect of IGF-I requires both PI3K- and MEK1-dependent pathways leading to the activation of the transcription factor CREB, which then induces the expression of the antiapoptotic factor bcl-2.

[1]  G. V. Vande Woude,et al.  Anti-apoptotic signaling by hepatocyte growth factor/Met via the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[2]  R. Kitsis,et al.  The MEK1–ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice , 2000, The EMBO journal.

[3]  D. Leroith,et al.  Extracellular regulated kinase, but not protein kinase C, is an antiapoptotic signal of insulin-like growth factor-1 on cultured cardiac myocytes. , 2000, Biochemical and biophysical research communications.

[4]  K. Heidenreich,et al.  Akt/Protein Kinase B Up-regulates Bcl-2 Expression through cAMP-response Element-binding Protein* , 2000, The Journal of Biological Chemistry.

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

[6]  C. M. Davenport,et al.  Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. , 1999, Science.

[7]  R. Hajjar,et al.  Adenoviral gene transfer of activated phosphatidylinositol 3'-kinase and Akt inhibits apoptosis of hypoxic cardiomyocytes in vitro. , 1999, Circulation.

[8]  S. R. Datta,et al.  Cellular survival: a play in three Akts. , 1999, Genes & development.

[9]  S. R. Datta,et al.  Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. , 1999, Science.

[10]  S. Ogawa,et al.  Characterization of insulin-like growth factor-1-induced activation of the JAK/STAT pathway in rat cardiomyocytes. , 1999, Circulation research.

[11]  K. Heidenreich,et al.  Insulin-like Growth Factor-I Induces bcl-2 Promoter through the Transcription Factor cAMP-Response Element-binding Protein* , 1999, The Journal of Biological Chemistry.

[12]  J. Romashkova,et al.  NF-κB is a target of AKT in anti-apoptotic PDGF signalling , 1999, Nature.

[13]  Min-Liang Kuo,et al.  The Antiapoptotic Gene mcl-1 Is Up-Regulated by the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway through a Transcription Factor Complex Containing CREB , 1999, Molecular and Cellular Biology.

[14]  R Dietz,et al.  E2F-1 overexpression in cardiomyocytes induces downregulation of p21CIP1 and p27KIP1 and release of active cyclin-dependent kinases in the presence of insulin-like growth factor I. , 1999, Circulation research.

[15]  R. Dietz,et al.  Signaling pathways in reactive oxygen species-induced cardiomyocyte apoptosis. , 1999, Circulation.

[16]  M. Welham,et al.  Dissociation of Apoptosis from Proliferation, Protein Kinase B Activation, and BAD Phosphorylation in Interleukin-3-mediated Phosphoinositide 3-Kinase Signaling* , 1999, The Journal of Biological Chemistry.

[17]  Susan S. Taylor,et al.  Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A. , 1999, Molecular cell.

[18]  M. Greenberg,et al.  Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor , 1999, Cell.

[19]  M. K. Meintzer,et al.  Insulin-like Growth Factor I-mediated Activation of the Transcription Factor cAMP Response Element-binding Protein in PC12 Cells , 1999, The Journal of Biological Chemistry.

[20]  M. C. Cardoso,et al.  E 2 F-1 Overexpression in Cardiomyocytes Induces Downregulation of p 21 CIP 1 and p 27 KIP 1 and Release of Active Cyclin-Dependent Kinases in the Presence of Insulin-Like Growth Factor I , 1999 .

[21]  M. Montminy,et al.  CREB Is a Regulatory Target for the Protein Kinase Akt/PKB* , 1998, The Journal of Biological Chemistry.

[22]  John Calvin Reed,et al.  Regulation of cell death protease caspase-9 by phosphorylation. , 1998, Science.

[23]  G. Cooper,et al.  Role of Glycogen Synthase Kinase-3 in the Phosphatidylinositol 3-Kinase/Akt Cell Survival Pathway* , 1998, The Journal of Biological Chemistry.

[24]  S. Izumo,et al.  Apoptosis: basic mechanisms and implications for cardiovascular disease. , 1998, Circulation research.

[25]  R. Lang,et al.  Dilated cardiomyopathy in transgenic mice expressing a dominant-negative CREB transcription factor in the heart. , 1998, The Journal of clinical investigation.

[26]  Y. Fujio,et al.  Activation of Phosphatidylinositol 3-Kinase through Glycoprotein 130 Induces Protein Kinase B and p70 S6 Kinase Phosphorylation in Cardiac Myocytes* , 1998, The Journal of Biological Chemistry.

[27]  J. Kornhauser,et al.  Nerve Growth Factor Activates Extracellular Signal-Regulated Kinase and p38 Mitogen-Activated Protein Kinase Pathways To Stimulate CREB Serine 133 Phosphorylation , 1998, Molecular and Cellular Biology.

[28]  R. Dietz,et al.  Differential effect of hydrogen peroxide and superoxide anion on apoptosis and proliferation of vascular smooth muscle cells. , 1997, Circulation.

[29]  L. Cantley,et al.  Conditional Inhibition of the Mitogen-activated Protein Kinase Cascade by Wortmannin , 1997, The Journal of Biological Chemistry.

[30]  S. R. Datta,et al.  Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death Machinery , 1997, Cell.

[31]  E. Lakatta,et al.  p53 and the hypoxia-induced apoptosis of cultured neonatal rat cardiac myocytes. , 1997, The Journal of clinical investigation.

[32]  K. Chien,et al.  Cardiotrophin 1 (CT-1) Inhibition of Cardiac Myocyte Apoptosis via a Mitogen-activated Protein Kinase-dependent Pathway , 1997, The Journal of Biological Chemistry.

[33]  G. Evan,et al.  Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB , 1997, Nature.

[34]  D. Leroith,et al.  Insulin-like Growth Factor 1 Inhibits Apoptosis Using the Phosphatidylinositol 3′-Kinase and Mitogen-activated Protein Kinase Pathways* , 1997, The Journal of Biological Chemistry.

[35]  D. Leroith,et al.  Insulin-like growth factor-1 inhibition of apoptosis is associated with increased expression of the bcl-xL gene product. , 1997, Endocrinology.

[36]  Elizabeth Yang,et al.  Serine Phosphorylation of Death Agonist BAD in Response to Survival Factor Results in Binding to 14-3-3 Not BCL-XL , 1996, Cell.

[37]  Michael E. Greenberg,et al.  Coupling of the RAS-MAPK Pathway to Gene Activation by RSK2, a Growth Factor-Regulated CREB Kinase , 1996, Science.

[38]  A. Klippel,et al.  Membrane localization of phosphatidylinositol 3-kinase is sufficient to activate multiple signal-transducing kinase pathways , 1996, Molecular and cellular biology.

[39]  H. Scheld,et al.  cAMP response element binding protein is expressed and phosphorylated in the human heart. , 1995, Circulation.

[40]  W. Fantl,et al.  Ras-dependent induction of cellular responses by constitutively active phosphatidylinositol-3 kinase. , 1995, Science.

[41]  S. Korsmeyer,et al.  Bad, a heterodimeric partner for Bcl-xL and Bcl-2, displaces bax and promotes cell death , 1995, Cell.

[42]  R. Kloner,et al.  Reperfusion injury induces apoptosis in rabbit cardiomyocytes. , 1994, The Journal of clinical investigation.

[43]  B. Ursø,et al.  The Insulin-Like Growth Factor-I Receptor , 1994, Hormone Research.

[44]  B. Ursø,et al.  The insulin-like growth factor-I receptor. Structure, ligand-binding mechanism and signal transduction. , 1994, Hormone research.

[45]  P. Sawchenko,et al.  Somatotroph hypoplasia and dwarfism in transgenic mice expressing a non-phosphorylatable CREB mutant , 1991, Nature.

[46]  V. Mitev,et al.  [Insulin-like growth factors]. , 1990, Eksperimentalna meditsina i morfologiia.