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 express ion of cardiac transcription factors and beating cardiomyocytes in non-prec ardiac mesodermal cells, suggesting that BMP-2 is an inductive signaling mo lecule that participates in cardiac development. However, direct evidence o f the effects of BMP-2 on cardiac myocytes has not been reported. To examin e the role of BMP-2 and its receptors, we studied the ability of BMP-2 to p romote 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 di d not strongly induce hypertrophic growth. To explore the mechanisms for th is protective effect, an adenovirus-based vector system was used. Similar t o 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 my ocytes by induction of Bcl-x(L) via a Smad1 pathway and might be a novel su rvival factor without any hypertrophic effect on myocytes.