Abstract
Background:
We recently reported that the activation of glycoprotein (gp) 130 by leukemia inhibitory factor (LIF) upregulates Bcl-xL and exerts antiapoptotic effects in cardiac myocytes. In addition, LIF induces activation of phosphatidylinositol (PI) 3-kinase and Akt, which are known to be required for cell survival. However, their regulatory roles in cell death remain unknown.
Methods and results:
We investigated the fate of these proteins and the cytoprotective effects of LIF on doxorubicin (DOX)-induced apoptosis in cultured neonatal rat cardiac myocytes. Myocyte apoptosis increased significantly in DOX-treated cells but was significantly reduced by LIF pretreatment. The kinase activities of PI 3-kinase and Akt declined below basal levels but were partially recovered with LIF. Moreover, DOX-induced caspase-3 activation and decrease in Bcl-xL abundance are completely inhibited by LIF and caspase inhibitor. LIF phosphorylates Bad through PI 3-kinase and reduces the heterodimerization of Bad with Bcl-xL. Adenovirus transfer of the constitutively active form of Akt to cardiac myocytes restored cardiac myocyte survival after DOX treatment. Conversely, the dominant-negative form of Akt inhibited LIF-induced increase in cell viability and suppression of caspase-9 activation.
Conclusions:
Activation of gp130 inhibits DOX-induced cell death in cardiac myocytes, resulting in the restoration of PI 3-kinase/Akt activities and in the inactivation of caspase-3, leading to facilitation of the protective function of Bcl-xL.
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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Antigens, CD / metabolism*
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Apoptosis / drug effects*
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Carrier Proteins / metabolism
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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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Cytokine Receptor gp130
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DNA Fragmentation / drug effects
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Dose-Response Relationship, Drug
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Doxorubicin / pharmacology*
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Enzyme Activation / drug effects
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Enzymes / metabolism*
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Growth Inhibitors / pharmacology
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Heart Ventricles / cytology
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Heart Ventricles / drug effects*
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Heart Ventricles / metabolism
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In Situ Nick-End Labeling
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Interleukin-6*
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Leukemia Inhibitory Factor
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Leukemia Inhibitory Factor Receptor alpha Subunit
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Lymphokines / pharmacology
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Membrane Glycoproteins / metabolism*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / drug effects
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Protein Binding
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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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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Rats
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Rats, Sprague-Dawley
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Receptors, Cytokine / metabolism
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Receptors, OSM-LIF
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bcl-Associated Death Protein
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bcl-X Protein
Substances
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Antigens, CD
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Bad protein, rat
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Bcl2l1 protein, rat
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Carrier Proteins
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Enzymes
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Growth Inhibitors
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Il6st protein, rat
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Interleukin-6
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Leukemia Inhibitory Factor
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Leukemia Inhibitory Factor Receptor alpha Subunit
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Lifr protein, rat
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Lymphokines
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Membrane Glycoproteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Cytokine
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Receptors, OSM-LIF
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bcl-Associated Death Protein
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bcl-X Protein
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Cytokine Receptor gp130
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Doxorubicin
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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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Casp3 protein, rat
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Caspase 3
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Caspases