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Ischemia-induced STAT-1 expression and activation play a critical role in cardiomyocyte apoptosis
A Stephanou1, B K Brar, T M Scarabelli
1Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom. Stephanov@yahoo.com
Abstract:
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.
Insights
Signal transducer and activator of transcription 1 (STAT-1) activation promotes cardiac cell death during ischemia/reperfusion. STAT-1 plays a critical role in regulating this apoptosis, partly through caspase-1 activation.
Area of Science:
- Cardiovascular Biology
- Cellular Signaling
- Apoptosis Research
Background:
- Ischemia/reperfusion injury is a major cause of cardiac damage.
- The precise molecular mechanisms regulating cardiac cell death during ischemia are not fully understood.
- Signal transducer and activator of transcription 1 (STAT-1) is implicated in cellular stress responses.
Purpose of the Study:
- To investigate the role of STAT-1 in ischemia/reperfusion-induced apoptosis in cardiac cells.
- To elucidate the signaling pathways involved in STAT-1-mediated cardiac cell death.
Main Methods:
- Simulated ischemia and interferon-gamma treatment of cardiac cells.
- Gene transfection with STAT-1 and antisense vectors.
- Caspase-1 promoter activity assays.
- Ex vivo ischemia/reperfusion studies in intact hearts.
- Immunofluorescence and TUNEL staining.
Main Results:
- Simulated ischemia induced cardiac cell apoptosis, accompanied by increased STAT-1 phosphorylation, expression, and transcriptional activity.
- STAT-1 overexpression enhanced susceptibility to ischemia-induced cell death, while antisense STAT-1 reduced it.
- Both STAT-1 activation and ischemia/reperfusion activated caspase-1 promoter activity in cardiomyocytes.
- STAT-1 activation and caspase-1 processing were observed in ventricular myocytes during ex vivo ischemia/reperfusion.
- STAT-1 upregulation co-localized with apoptotic cells in response to ischemia/reperfusion.
Conclusions:
- STAT-1 plays a critical role in regulating ischemia/reperfusion-induced apoptosis in cardiac cells.
- The pro-apoptotic effects of STAT-1 are mediated, at least in part, via the caspase-1 activation pathway.
- Targeting STAT-1 may offer a therapeutic strategy for mitigating cardiac injury during ischemia/reperfusion events.