Mitogen-activated Protein Kinases p38 and ERK 1/2 Mediate the Wall Stress-induced Activation of GATA-4 Binding in Adult Heart

Abstract

The zinc finger transcription factor GATA-4 has been implicated as a critical regulator of inducible cardiac gene expression and as a potential mediator of the hypertrophic program. However, the precise intracellular mechanisms that regulate the DNA-binding activity of GATA-4 are not fully understood. The aim of the present study was to examine the role of mitogen-activated protein kinases (p38 kinase, extracellular signal-regulated protein kinase, and c-Jun N-terminal protein kinase) in the left ventricular wall stress-induced activation of GATA-4 DNA binding in adult heart. Isolated perfused rat hearts were subjected to increased left ventricular wall stress by inflating a balloon in the ventricle. Gel mobility shift assays were used to analyze the transacting factors that interact with the GATA motifs of the B-type natriuretic peptide promoter. The left ventricular wall stress rapidly activated GATA-4 DNA binding and significantly increased the levels of phosphorylated p38 kinase, extracellular signal-regulated protein kinase, and c-Jun N-terminal protein kinase. The wall stress-induced increase in the DNA-binding activity of GATA-4 was abolished both in the presence of the p38 inhibitor SB239063 and MEK1/2 inhibitor U0126. In contrast, the inhibition of c-Jun N-terminal protein kinase by CEP11004 had no effect on the baseline or stretchinduced GATA-4 DNA binding. Moreover, GATA-4 DNA binding was up-regulated by mechanical stretch in the isolated rat atria via p38 and extracellular signal-regulated protein kinase. In conclusion, the present study demonstrates that both p38 and extracellular signalregulated protein kinase are required for the stretchinduced GATA-4 binding in intact heart.

Treatment with an adenoviral vector encoding hepatocyte growth factor mitigates established cardiac dysfunction in doxorubicin-induced cardiomyopathy

“…Our findings suggest that altered signaling via ERK, but not Akt, is involved in doxorubicin-induced cardiomyopathy, which is consistent with a recent study showing that ERK activation is significantly diminished during the chronic stage of doxorubicin-induced cardiomyopathy (3 wk after doxorubicin administration) (20). Given that another study, in which isolated rat heart was subjected to excessive LV wall stress (induced by balloon inflation), showed MAPK (p38 and ERKs) to be involved in the activation of GATA-4 binding to DNA (35), we suggest that HGF exerts its cardioprotective effects by restoring activity in ERK/MAPK signaling pathway.…”

Mitochondrial Reactive Oxygen Species Mediate Cardiomyocyte Formation from Embryonic Stem Cells in High Glucose

“…This phosphorylation is a prerequisite for Mef2c translocation to the nucleus [47]. (b) Similarly, Gata4 phosphorylation by p38 MAPK increases its DNA-binding in the stress-induced adult heart [49], and greatly increases Gata4 transcriptional activity during sarcomeric organization [50]. The fact that Gata4 and also Mef2c were mislocalized to the cytosolic compartment under low glucose conditions suggests this possibility.…”

Oncogenic Ras upregulates NADPH oxidase 1 gene expression through MEK-ERK-dependent phosphorylation of GATA-6

“…Other members of the GATA transcription factor family have been shown to exist as phosphoproteins. For example, GATA-1 is phosphorylated in erythroid cells by ERK upon erythropoietin stimulation (HernandezHernandez et al, 2006) and GATA-4 is phosphorylated in cardiac myocytes by ERK/p38 MAPK in response to hypertrophic stimuli (Tenhunen et al, 2004) or ERK following hepatocyte growth factor stimulation (Kitta et al, 2003). These phosphorylation events commonly activate the DNA-binding activity of the GATA family proteins.…”