Abstract
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.
Highlights
The transcription factor GATA4 is essential in pathological cardiac hypertrophy
Insulin-like growth factor 1 (IGF1)- and PE-induced Hypertrophy Is Associated with Activation of GATA4—We compared the growth-promoting effects of 10 nmol/liter IGF1 and 20 mol/liter PE on neonatal rat ventricular cardiomyocytes
A total of Ͼ600 cells from five independent cultures were examined for cell size. Both agonists resulted in significant increases in cell size (PE by 48 Ϯ 7% and IGF1 by 62 Ϯ 9%) and in protein synthesis (Fig. 1, A and B). These effects were associated with increased GATA4 binding activity as indicated by two types of evidence: (a) ELISA assay and (b) chromatin IP (ChIP) with consecutive Quantitative real-time PCR (qRT-PCR) for quantification of specific GATA4 binding to the promoter regions of previously reported GATA4 target genes
Summary
The transcription factor GATA4 is essential in pathological cardiac hypertrophy. Results: The physiological stimulus IGF1 increased GATA4 activity but did not require GATA4 for the induction of hypertrophy. IGF1 has an ability to inhibit signaling cascades that are activated in models of pathological hypertrophy (e.g. downstream of GPCR) [10] Based on these beneficial cellular actions, the IGF1/PI3K pathway has been considered as a therapeutic agent in heart disease, where it could potentially modulate hypertrophy toward a more physiological type and improve myocyte survival and function. IGF1 inhibits glycogen synthase kinase-3 (GSK3) [19] and activates Mek and ERK1/2 in cardiac myocytes in vitro [20] Because both GSK3 and ERK1/2 influence GATA4 transcription factor activity [21, 22], we hypothesized that GATA4 might be downstream of IGF1 and an important mediator of its growth and protective effects in cardiomyocytes. This reveals an important difference in the underlying mediators of pathological versus physiological type of cardiac hypertrophy
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