Growth differentiation factor 15 acts anti-apoptotic and pro-hypertrophic in adult cardiomyocytes.
Growth differentiation factor 15 (GDF15) is induced during heart failure development, and may influence different processes in cardiac remodeling. While its anti-apoptotic action under conditions of ischemia-reperfusion have been shown, it remained unclear if this is a broadly protective effect applicable to other apoptotic stimuli. Furthermore, effects on cardiac hypertrophy remained obscure. Therefore, we investigated the effects of GDF15 on induction of hypertrophy and apoptosis in ventricular cardiomyocytes. GDF15 (3 ng/ml) enhanced hypertrophic growth of cardiomyocytes as determined by an increase in cell size by 27 +/- 5% and rate of protein synthesis by 47 +/- 15%. In addition, a time and dose-dependent increase in SMAD-binding affinity was found, as well as enhanced phosphorylation of R-SMAD1. Inhibition of SMADs by transformation of cardiomyocytes with SMAD-decoy oligonucleotides abolished the hypertrophic growth effect. Specific inhibitors of PI3K (10 microM LY290042 or 10 nM wortmannin) or ERK (10 microM PD98059) also blocked GDF15-induced hypertrophy and SMAD activation. Apoptosis induction by three different agents, 100 nM angiotensin II, 1 ng/ml TGFbeta(1), or the NO-donor SNAP (100 microM) was blocked by addition of GDF15 (3 ng/ml). Scavenging of SMADs by transformation of cardiomyocytes with SMAD-decoy oligonucleotides abolished the anti-apoptotic effect of GDF15. In conclusion, GDF15 protects ventricular cardiomyocytes against different apoptotic stimuli and enhances hypertrophic growth. Hypertrophic signaling is thereby mediated via the kinases PI3K and ERK and the transcription factor R-SMAD1. Thus, GDF15 may influence cardiac remodeling via two different mechanisms, apoptosis protection and induction of hypertrophy.
Physiologisches Institut, Justus-Liebig-Universität Giessen, Giessen, Germany.
J
J
Heger
E
E
Schiegnitz
D
D
von Waldthausen
M M
MM
Anwar
H M
HM
Piper
G
G
Euler
D000367:Age Factors; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D055436:Growth Differentiation Factor 15 / Q000378:metabolism*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009841:Oligonucleotides / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D020257:Ventricular Remodeling
D000804:Angiotensin II; D048049:Extracellular Signal-Regulated MAP Kinases; D055436:Growth Differentiation Factor 15; D020030:Nitric Oxide Donors; D009841:Oligonucleotides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051898:Smad1 Protein; D053773:Transforming Growth Factor beta1; C497400:Smad1 protein, rat