IGF-1 protects cardiac myocytes from hyperosmotic stress-induced apoptosis via CREB.
Hyperosmotic stress stimulates a rapid and pronounced apoptosis in cardiac myocytes which is attenuated by insulin-like growth factor-1 (IGF-1). Because in these cells IGF-1 induces intracellular Ca(2+) increase, we assessed whether the cyclic AMP response element-binding protein (CREB) is activated by IGF-1 through Ca(2+)-dependent signalling pathways. In cultured cardiac myocytes, IGF-1 induced phosphorylation (6.5 +/- 1.0-fold at 5 min), nuclear translocation (30 min post-stimulus) and DNA binding activity of CREB. IGF-1-induced CREB phosphorylation was mediated by MEK1/ERK, PI3-K, p38-MAPK, as well as Ca(2+)/calmodulin kinase and calcineurin. Exposure of cardiac myocytes to hyperosmotic stress (sorbitol 600 mOsm) decreased IGF-1-induced CREB activation Moreover, overexpression of a dominant negative CREB abolished the anti-apoptotic effects of IGF-1. Our results suggest that IGF-1 activates CREB through a complex signalling pathway, and this transcription factor plays an important role in the anti-apoptotic action of IGF-1 in cultured cardiac myocytes.
Maldonado
Carola
C
Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago.
Cea
Paola
P
Adasme
Tatiana
T
Collao
Andrés
A
Díaz-Araya
Guillermo
G
Chiong
Mario
M
Lavandero
Sergio
S
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019703:Calcineurin / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000502:physiology*; D009997:Osmotic Pressure; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D019703:Calcineurin