Circulation. 2001;104:2088-2094
doi: 10.1161/hc4201.097133
doi: 10.1161/hc4201.097133
(Circulation. 2001;104:2088.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
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
From the Department of Cardiology (F.B.M., M.W.B., P.L., R.D., R.v.H.), Franz Volhard Clinic, Humboldt-University, Berlin, and Institute for Pharmacology and Toxicology (F.-U.M., W.S), University Münster, Münster, Germany; and the Department of Physiology (Y.W.), University of Maryland, Baltimore, Md.
Correspondence to Rüdiger von Harsdorf, MD, Universitätsklinikum Charité, Medizinische Klinik mit Schwerpunkt Kardiologie, Humboldt-Universität, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail ruediger.harsdorf{at}charite.de
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.
Key Words: apoptosis • hypoxia • signal transduction • growth factors
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