Transcription factor GATA4 is activated but not required for insulin-like growth factor 1 (IGF1)-induced cardiac hypertrophy.
Insulin-like growth factor 1 (IGF1) promotes a physiological type of cardiac hypertrophy and has therapeutic effects in heart disease. Here, we report the relationship of IGF1 to GATA4, an essential transcription factor in cardiac hypertrophy and cell survival. In cultured neonatal rat ventricular myocytes, we compared the responses to IGF1 (10 nmol/liter) and phenylephrine (PE, 20 μmol/liter), a known GATA4 activator, in concentrations promoting a similar extent of hypertrophy. IGF1 and PE both increased nuclear accumulation of GATA4 and phosphorylation at Ser(105) (PE, 2.4-fold; IGF1, 1.8-fold; both, p < 0.05) and increased GATA4 DNA binding activity as indicated by ELISA and by chromatin IP of selected promoters. Although IGF1 and PE each activated GATA4 to the same degree, GATA4 knockdown by RNA interference only blocked hypertrophy by PE but not by IGF1. PE induction of a panel of GATA4 target genes (Nppa, Nppb, Tnni3, Myl1, and Acta1) was inhibited by GATA4 knockdown. In contrast, IGF1 regulated only Acta1 in a GATA4-dependent fashion. Consistent with the in vitro findings, Gata4 haploinsufficiency in mice did not alter cardiac structure, hyperdynamic function, or antifibrotic effects induced by myocardial overexpression of the IGF1 receptor. Our data indicate that GATA4 is activated by the IGF1 pathway, but although it is required for responses to pathological stimuli, it is not necessary for the effects of IGF1 on cardiac structure and function.
Department of Cardiology, Medical University Graz, Auenbruggerplatz 15, 8036 Graz, Austria,; Department of Cardiology and Pneumology, Georg August University, Robert Koch Str. 40, 37075 Göttingen, Germany.
Egbert
E
Bisping
Department of Cardiology, Children's Hospital Boston, Boston, Massachusetts 02115.
Sadakatsu
S
Ikeda
Department of Cardiology and Pneumology, Georg August University, Robert Koch Str. 40, 37075 Göttingen, Germany.
Miriam
M
Sedej
Department of Cardiology, Medical University Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
Paulina
P
Wakula
Baker IDI Heart and Diabetes Research Institute, 6492 St. Kilda Road Central, Melbourne, Victoria 8008, Australia.
Julie R
JR
McMullen
Novartis Institute for Biomedical Research, Cambridge, Massachusetts 02139, and.
Oleg
O
Tarnavski
Department of Cardiology, Medical University Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
Simon
S
Sedej
CVM Consulting, Brookline, Massachusetts 02445.
Seigo
S
Izumo
Department of Cardiology, Children's Hospital Boston, Boston, Massachusetts 02115.
William T
WT
Pu
Department of Cardiology, Medical University Graz, Auenbruggerplatz 15, 8036 Graz, Austria,; Department of Cardiology and Pneumology, Georg August University, Robert Koch Str. 40, 37075 Göttingen, Germany,. Electronic address: burkert.pieske@medunigraz.at.
Burkert
B
Pieske
D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000009:adverse effects* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar
D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; C084365:Gata4 protein, rat; C519530:insulin-like growth factor-1, mouse; C548904:insulin-like growth factor-1, rat; D007334:Insulin-Like Growth Factor I