Apoptotic effects of TGFbeta superfamily members in isolated adult rat cardiomyocytes
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Institut f├╝r Physiologie
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Several TGFbeta family members are upregulated in the heart by increased work load after myocardial infarction. Therefore, their expressions correlate with cardiac apoptosis induction in vivo. I have now tested in this study, if TGFbeta superfamily members induce apoptosis in ventricular cardiomyocytes of rat.
Cardiomyocytes were stimulated with TGFbeta, myostatin, BMP-2, activin A or GDF15. Apoptosis was determined by detection of chromatin condensation and DNA laddering. Apoptosis was induced by TGFbeta, myostatin, activin A and BMP-2. A classical signaling molecule of TGF beta family members is the transcription factor SMAD, which is able to interact with AP-1, a factor known to mediate apoptosis in cardiomyocytes after NO stimulation. In retardation assays I have now demonstrated that AP-1 and SMAD binding were activated by TGFbeta, myostatin, BMP-2 or activin A. Intracellular scavenging of SMAD or AP-1 binding activity by transformation of cardiomyocytes with SMAD-decoy oligos or AP-1 decoy oligos inhibited apoptosis induction by TGF beta, myostatin, BMP-2 or activin A.
GDF15 stimulates SMAD binding activity similar to the other family members. But in contrast to them GDF15 showed anti-apoptotic effects. It inhibited apoptosis induction by TGFbeta.
Conclusions: Most of the investigated TGFbeta-superfamily members activate the transcription factors AP-1 and SMAD and induce apoptosis in cardiomyocytes. For TGFbeta, myostatin, BMP-2 and activin-A SMAD/AP-1 is a common pathway for apoptosis induction in cardiomyocytes. GDF 15 has anti-apoptotic effects and inhibits TGF beta induced apoptosis. Therefore, further investigations on GDF15 signaling may have potential to discover now anti-apoptotic therapies in heart.
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