Abstract
In this study we have determined the ability of IGF-1 to protect cardiac fibroblasts against osmotic-induced apoptosis and investigated the potential mechanism(s) underlying this protection. Treatment with IGF-1 (1-100 ng/ml) promoted a dose dependent increase in cell survival against osmotic cell death. Both Akt and ERK1/2 were rapidly phosphorylated by IGF-1 and blocked by wortmannin and PD98059, inhibitors of their upstream activators respectively. However, IGF-1-induced protection was mediated via a wortmannin-dependent but PD98059-independent pathway as determined by cell survival assay suggesting a role of PI3-K/Akt. Furthermore, IGF-1 appeared to reduce the activation of a number of early components in the apoptotic pathway in a wortmannin dependent manner including the osmotic stress-induced perturbation in mitochondrial membrane potential, cleavage and activation of caspase-3 and DNA fragmentation. Thus, the results suggest that IGF-1 regulates osmotic stress-induced apoptosis via the activation of the PI3-K/Akt pathway at a point upstream of the mitochondria and caspase-3.
Copyright 2000 Academic Press.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Apoptosis / drug effects*
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Caspase 3
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Caspases / metabolism
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Cell Survival / drug effects
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Cells, Cultured
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DNA Fragmentation / drug effects
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Dose-Response Relationship, Drug
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Enzyme Activation / drug effects
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Fibroblasts / cytology*
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Fibroblasts / drug effects*
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Fibroblasts / enzymology
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Fibroblasts / metabolism
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Insulin-Like Growth Factor I / antagonists & inhibitors
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Insulin-Like Growth Factor I / pharmacology*
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Isoenzymes / chemistry
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Isoenzymes / metabolism
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Membrane Potentials / drug effects
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Mitochondria / drug effects
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Mitochondria / physiology
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Myocardium / cytology*
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Osmolar Concentration
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Peptide Fragments / chemistry
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Peptide Fragments / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Protein Kinase C / chemistry
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Protein Kinase C / metabolism
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Protein Kinase C-delta
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Rats
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Signal Transduction / drug effects
Substances
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Isoenzymes
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Peptide Fragments
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Insulin-Like Growth Factor I
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Prkcd protein, rat
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Akt1 protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Protein Kinase C
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Protein Kinase C-delta
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Mitogen-Activated Protein Kinases
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Casp3 protein, rat
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Caspase 3
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Caspases