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.
Suzuki
Yuichiro J
YJ
Department of Pharmacology, Georgetown University Medical Center, NW403 Medical-Dental Building, 3900 Reservoir Road NW, Washington, DC 20057, USA. ys82@georgetown.edu
Nagase
Hiroko
H
Day
Regina M
RM
Das
Dipak K
DK
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002227:Carbazoles / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D050991:GATA4 Transcription Factor; D007211:Indoles / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*
D002227:Carbazoles; D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D007211:Indoles; D014157:Transcription Factors; C073601:KT 5823; D009569:Nitric Oxide; D017869:Cyclic GMP-Dependent Protein Kinases