Abstract
Bone morphogenetic protein (BMP)-2 has been shown to induce ectopic expression of cardiac transcription factors and beating cardiomyocytes in non-precardiac mesodermal cells, suggesting that BMP-2 is an inductive signaling molecule that participates in cardiac development. However, direct evidence of the effects of BMP-2 on cardiac myocytes has not been reported. To examine the role of BMP-2 and its receptors, we studied the ability of BMP-2 to promote survival of isolated neonatal rat cardiac myocytes. BMP receptors IA, IB, and II and activin receptor I were found to be expressed in myocytes, and BMP-2 phosphorylated Smad1 and p38 MAPK. Interestingly, BMP-2 promoted survival and inhibited apoptosis of serum-deprived myocytes, although it did not strongly induce hypertrophic growth. To explore the mechanisms for this protective effect, an adenovirus-based vector system was used. Similar to BMP-2, Smad1 promoted survival that was repressed by Smad6. Moreover, BMP-2 and Smad1 enhanced the expression of the anti-apoptotic molecule Bcl-x(L). Antisense oligonucleotides to bcl-x(L) attenuated the survival effected by BMP-2. Overall, our findings suggest that BMP-2 prevents apoptosis of myocytes by induction of Bcl-x(L) via a Smad1 pathway and might be a novel survival factor without any hypertrophic effect on myocytes.
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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Bone Morphogenetic Protein 2
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Bone Morphogenetic Protein Receptors
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Bone Morphogenetic Proteins / genetics
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Bone Morphogenetic Proteins / pharmacology*
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Cardiomegaly / chemically induced
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Cells, Cultured
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Culture Media, Serum-Free
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DNA-Binding Proteins / physiology*
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Mitogen-Activated Protein Kinases / physiology
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Myocardium / pathology*
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Oligonucleotides, Antisense / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / physiology
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Rats
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Rats, Wistar
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Receptors, Cell Surface / genetics
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Receptors, Growth Factor*
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Reverse Transcriptase Polymerase Chain Reaction
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Smad Proteins
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Smad1 Protein
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Smad6 Protein
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Trans-Activators / physiology*
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Transforming Growth Factor beta*
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bcl-X Protein
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p38 Mitogen-Activated Protein Kinases
Substances
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Bcl2l1 protein, rat
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Bmp2 protein, rat
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Bone Morphogenetic Protein 2
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Bone Morphogenetic Proteins
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Culture Media, Serum-Free
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DNA-Binding Proteins
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Oligonucleotides, Antisense
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Cell Surface
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Receptors, Growth Factor
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Smad Proteins
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Smad1 Protein
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Smad1 protein, rat
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Smad6 Protein
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Smad6 protein, rat
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Trans-Activators
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Transforming Growth Factor beta
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bcl-X Protein
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Bone Morphogenetic Protein Receptors