Ischemia-induced STAT-1 expression and activation play a critical role in cardiomyocyte apoptosis.
We show here that exposure of cardiac cells to simulated ischemia results in apoptosis and is accompanied by phosphorylation and increased expression and transcriptional activity of STAT-1. Similarly, interferon-gamma, which is known to induce STAT-1 activation, also induced apoptosis in cardiac cells. STAT-1-transfected cells were more susceptible to ischemia-induced cell death than cells transfected with a control plasmid lacking the STAT-1 coding sequence. Furthermore, an antisense STAT-1 vector reduced both ischemia- and overexpressed STAT-1-induced cell death in cardiac cells. Both STAT-1 overexpression and interferon-gamma treatment or exposure to ischemia activated the promoter of the pro-apoptotic caspase-1 gene in cardiomyocytes. Finally, ischemia/reperfusion also induced STAT-1 activation and caspase-1 processing in ventricular myocytes in the intact heart ex vivo. Immunofluorescent staining demonstrated an increase in STAT-1-positive staining in cardiomyocytes in response to ischemia/reperfusion that co-localized with terminal deoxynucleotidyl transferase dVTP nick end-labeling-positive apoptotic cells. These results suggest that STAT-1 plays a critical role in the regulation of ischemia/reperfusion-induced apoptosis in cardiac cells, acting at least in part via a caspase-1 activation-dependent pathway.
Stephanou
A
A
Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom. Stephanov@yahoo.com
Brar
B K
BK
Scarabelli
T M
TM
Jonassen
A K
AK
Yellon
D M
DM
Marber
M S
MS
Knight
R A
RA
Latchman
D S
DS
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology / Q000503:physiopathology*; D006352:Heart Ventricles; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D017202:Myocardial Ischemia / Q000235:genetics* / Q000378:metabolism; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
D004268:DNA-Binding Proteins; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; D015534:Trans-Activators