GATA-4 regulation of myocardial survival in the preconditioned heart

Recent studies identified that GATA-4 is a stress responsive transcription factor and can exert cell survival signaling in cardiac myocytes. The present study was designed to examine whether GATA-4 is modulated by ischemic preconditioning (PC), and ischemia/reperfusion (I/R). PC of isolated rat hearts was elicited by perfusing with Krebs-Henseleit bicarbonate buffer with four cyclic episodes of 5 min ischemia and 10 min reperfusion. Some hearts were then subjected to 30 min ischemia followed by 2 h reperfusion. PC increased the DNA binding activity of GATA-4 compared to control, while I/R downregulated GATA-4 expression. Activation was associated with post-translational modifications of GATA-4 via acetylation. As nitric oxide (NO) may be involved in PC and I/R, we examined whether NO could modulate GATA-4 in HL-1 cardiac muscle cells. An NO donor, sodium nitroprusside (SNP), downregulated GATA activity and GATA-4 mRNA expression. We cloned the 5'-flanking region of human GATA-4 gene and found that the luciferase activity controlled by this region was also suppressed by NO. A protein kinase G (PKG) inhibitor KT5823 inhibited SNP-induced downregulation of GATA-4, while YC-1 (guanylyl cyclase activator) and dibutyryl cGMP (PKG activator) downregulated GATA-4. Thus, GATA-4 is modulated by PC, I/R and NO, and might regulate cardiac myocyte survival and apoptosis.