Transcription Factor GATA4 Is Activated but Not Required for Insulin-like Growth Factor 1 (IGF1)-induced Cardiac Hypertrophy

• Published in: The Journal of biological chemistry 2012-03, Vol.287 (13), p.9827-9834
• Main Authors: Bisping, Egbert, Ikeda, Sadakatsu, Sedej, Miriam, Wakula, Paulina, McMullen, Julie R., Tarnavski, Oleg, Sedej, Simon, Izumo, Seigo, Pu, William T., Pieske, Burkert
• Format: Article
• Language: English
• Subjects: Animals; Cardiac Hypertrophy; Cardiomegaly - chemically induced; Cardiomegaly - genetics; Cardiomegaly - metabolism; Cardiomegaly - pathology; Cardiomyocytes; Cell Culture; Cells, Cultured; Chromatin Immunoprecipitation (ChIP); GATA4 Transcription Factor - genetics; GATA4 Transcription Factor - metabolism; Gene Knockdown Techniques; Gene Regulation; Heart; Heart Ventricles - metabolism; Heart Ventricles - pathology; Insulin-Like Growth Factor I - adverse effects; Insulin-Like Growth Factor I - pharmacology; Mice; Mice, Knockout; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; NRVCM; NRVM; Promoter Regions, Genetic - genetics; Rats; Rats, Wistar; Signal Transduction; Transcription Target Genes
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.338749

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 Ser105 (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. The transcription factor GATA4 is essential in pathological cardiac hypertrophy. The physiological stimulus IGF1 also increased GATA4 activity but did not require GATA4 for the induction of hypertrophy. In contrast to pathological stimuli, IGF1 activates but does not require GATA4 for induction of hypertrophy. Therapeutic modulation of hypertrophy to a physiological pattern by IGF1 can be achieved independent of GATA4.