Bone morphogenetic protein-2 inhibits serum deprivation-induced apoptosis of neonatal cardiac myocytes through activation of the Smad1 pathway.
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.
Izumi
M
M
Department of Molecular Medicine, Osaka University Graduate School of Medicine, Suita City, Osaka 565-0871, Japan.
Fujio
Y
Y
Kunisada
K
K
Negoro
S
S
Tone
E
E
Funamoto
M
M
Osugi
T
T
Oshima
Y
Y
Nakaoka
Y
Y
Kishimoto
T
T
Yamauchi-Takihara
K
K
Hirota
H
H
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D055396:Bone Morphogenetic Protein 2; D052004:Bone Morphogenetic Protein Receptors; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000494:pharmacology*; D006332:Cardiomegaly / Q000139:chemically induced; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009206:Myocardium / Q000473:pathology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000235:genetics; D017978:Receptors, Growth Factor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051785:Smad Proteins; D051898:Smad1 Protein; D051905:Smad6 Protein; D015534:Trans-Activators / Q000502:physiology*; D016212:Transforming Growth Factor beta; D051020:bcl-X Protein; D048051:p38 Mitogen-Activated Protein Kinases
C494813:Bcl2l1 protein, rat; C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D011956:Receptors, Cell Surface; D017978:Receptors, Growth Factor; D051785:Smad Proteins; D051898:Smad1 Protein; C497400:Smad1 protein, rat; D051905:Smad6 Protein; C497804:Smad6 protein, rat; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D051020:bcl-X Protein; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D052004:Bone Morphogenetic Protein Receptors