The Transcription Factors GATA4 and GATA6 Regulate Cardiomyocyte Hypertrophy in Vitro and in Vivo

Abstract

The zinc finger-containing transcription factors GATA4 and GATA6 are important regulators of basal and inducible gene expression in cardiac and smooth muscle cell types. Here we demonstrate a direct functional role for GATA4 and GATA6 as regulators of cardiomyocyte hypertrophic growth and gene expression. To model the increase in endogenous GATA4 and GATA6 transcriptional activity that occurs in response to hypertrophic stimulation, each factor was overexpressed in cardiomyocytes using recombinant adenovirus. Overexpression of either GATA4 or GATA6 was sufficient to induce cardiomyocyte hypertrophy characterized by enhanced sarcomeric organization, a greater than 2-fold increase in cell surface area, and a significant increase in total protein accumulation. In vivo, transgenic mice with 2.5-fold overexpression of GATA4 within the adult heart demonstrated a slowly progressing increase in heart to body weight ratio, histological features of cardiomyopathy, and activation of hypertrophy-associated genes, suggesting that GATA factors are sufficient regulators of cardiomyocyte hypertrophy in vitro and in vivo. To evaluate the requirement of GATA factors as downstream transcriptional mediators of hypertrophy, a dominant negative GATA4-engrailed repressor fusionencoding adenovirus was generated. Expression of GATA4-engrailed blocked GATA4-and GATA6-directed transcriptional responses and agonist-induced cardiomyocyte hypertrophy, demonstrating that cardiac-expressed GATA factors are necessary mediators of this process.

Kruppel-like Factors (KLFs) in muscle biology

“…Cardiomyocytes from these MEF2-transgenic hearts have large and elongated myocytes [44] similar to those observed with KLF15-deficiency [27]. Transgenic overexpression of GATA4 in the heart at high levels results in a severe cardiomyopathy and premature death [45]. Even modest GATA4 overexpression results in a spontaneous cardiomyopathy characterized by increased heart mass and hypertrophic gene expression [45].…”

“…Transgenic overexpression of GATA4 in the heart at high levels results in a severe cardiomyopathy and premature death [45]. Even modest GATA4 overexpression results in a spontaneous cardiomyopathy characterized by increased heart mass and hypertrophic gene expression [45]. Given that MEF2 and GATA4 factors can cooperate and serve as integrators for multiple upstream signaling pathways, it is not surprising that heightened activity of these two factors leads to a marked decompensation in KLF15(−/−) mice in response to stress.…”

Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy

“…Cardiac-specific transgenic overexpression of either MEF2 (16,17) or constitutively active calcineurin-A (18) cause cardiomyopathies characterized by increased cardiac mass, chamber dilation, and left-ventricular systolic dysfunction. High levels of GATA4 overexpression in the heart also result in a severe cardiomyopathy and premature death, and modest overexpression results in cardiac hypertrophy (10). Multiple lines of evidence indicate that these transcriptional pathways cooperate in the development of cardiac dysfunction (16).…”

“…These studies have established that the hypertrophic response occurs through the activation of multiple cytosolic signaling pathways and nuclear factors (1,2,7). With respect to the latter, factors such as myocyte enhancer factor-2 (MEF2), GATA4, and nuclear factor of activated T cells (NFATs) have been implicated as key mediators of the hypertrophic transcriptional program (8)(9)(10)(11)(12)(13)(14)(15). Prohypertrophic stimuli activate a series of intracellular signal transduction pathways that result in the induction of MEF2 and GATA4 DNA-binding activity and nuclear accumulation of NFATs.…”

“…Prohypertrophic stimuli activate a series of intracellular signal transduction pathways that result in the induction of MEF2 and GATA4 DNA-binding activity and nuclear accumulation of NFATs. In vitro studies have demonstrated that overexpression of either MEF2 factors or GATA4 induces cardiomyocyte hypertrophy (10,16). Cardiac-specific transgenic overexpression of either MEF2 (16,17) or constitutively active calcineurin-A (18) cause cardiomyopathies characterized by increased cardiac mass, chamber dilation, and left-ventricular systolic dysfunction.…”