Activated STAT-1 pathway in the myocardium as a novel therapeutic target in ischaemia/reperfusion injury.
The signal transducers and activators of transcription (STAT) factors function as modulators of cytokine signaling and sensors responding to UV and ischaemic stress. Recently, we have reported a number of transcriptional mechanisms that induce expression of pro-apoptotic genes following ischaemia/reperfusion (I/R) in cardiac myocytes. For example, we have shown that STAT-1 plays a role in enhancing apoptotic cell death in cardiac myocytes exposed to I/R. In contrast to STAT-1, STAT-3, which is activated by the IL-6 cytokine family, has cardioprotective effects in cardiac myocytes exposed to I/R. The induction of apoptosis in cardiac myocytes by STAT-1 is dependent on STAT-1 phosphorylation on serine-727. Furthermore, we have demonstrated that the C-terminal transactivation domain of STAT-1 is required to mediate apoptotic cell death in cardiac myocytes exposed to I/R. Finally, cardiac myocytes isolated from mice expressing a truncated C-terminal STAT-1 were more sensitive to I/R-induced cell death. The isolated intact hearts from these animals exposed to I/R injury, had larger infarct size and a greater number of TUNEL-positive myocytes than control hearts. Hence, these studies demonstrate that activated STAT-1 is a pro-apoptotic factor in cardiac myocytes exposed to I/R, and is therefore a potential therapeutic target for the prevention of cell death following I/R injury.
Stephanou
Anastasis
A
Medical Molecular Biology Unit, Institute of Child Health, University College London, 30 Guilford Street, UK. a.stephanou@ich.ucl.ac.uk
D000818:Animals; D017209:Apoptosis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008955:Models, Cardiovascular; D017202:Myocardial Ischemia / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*
D004268:DNA-Binding Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators