The transcription factors GATA4 and GATA6 regulate cardiomyocyte hypertrophy in vitro and in vivo

The zinc finger-containing transcription factors GATA4 and GATA6 are import ant 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 expre ssion. To model the increase in endogenous GATA4 and GATA6 transcriptional activity that occurs in response to hypertrophic stimulation, each factor w as overexpressed in cardiomyocytes using recombinant adenovirus. Overexpres sion of either GATA4 or GATA6 was sufficient to induce cardiomyocyte hypert rophy characterized by enhanced sarcomeric organization, a greater than 2-f old increase in cell surface area, and a significant increase in total prot ein 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 ac tivation 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 med iators of hypertrophy, a dominant negative GATA4-engrailed repressor fusion -encoding adenovirus was generated. Expression of GATA4-engrailed blocked G ATA4- and GATA6-directed transcriptional responses and agonist-induced card iomyocyte hypertrophy, demonstrating that cardiac-expressed GATA factors ar e necessary mediators of this process.