Stress-induced Activation of GATA-4 in Cardiac Muscle Cells

GATA-4 regulates gene transcription in the heart. This study examined whether GATA-4 is influenced by stress-induced signaling events. Treatment of HL-1 cardiac muscle cells with mercury results in the induction of apoptosis that is blocked by overexpression of catalase. Similar to daunorubicin (DNR), mercury causes downregulation of GATA-4 mRNA expression. However, mercury is less effective in inducing apoptosis compared to DNR. Analyses of GATA-4 protein expression and activity reveal that mercury initially enhances the GATA-4 DNA-binding activity, before subsequent downregulation of GATA-4 expression. The mercury-induced GATA-4 activation is associated with a phosphorylation of GATA-4, which appears to occur via the MEK/ERK pathway. The level of phosphorylated GATA-4 is more slowly decreased by mercury or actinomycin D, compared to unphosphorylated GATA-4, suggesting that phosphorylated GATA-4 is more resistant to cellular degradation. Consistent with a previous finding that GATA-4 phosphorylation induces cell survival, mercury decreases cell death induced by DNR. These results suggest that cardiac muscle cells respond to mercury stress by eliciting MEK/ERK signaling to form phosphorylated GATA-4 that is more resistant to cellular degradation and induce cell survival.