Cardiovascular Research Advance Access [Accepted Manuscript] published online on March 13, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn067
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Dual activation of STAT-3 and Akt is required during the trigger phase of ischaemic preconditioning
Hatter Cardiovascular Research Institute, Dept of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa
Address for correspondence: Dr Sandrine Lecour Hatter Cardiovascular Research Institute Chris Barnard Building Faculty of Health Sciences Private Bag 3 7935 Observatory South Africa Tel: +27 21 406 6358 Fax: +27 21 447 8789 Email: sandrine.lecour{at}uct.ac.za
Aims: During preconditioning by tumor necrosis factor alpha (TNF
), activation of the signal transducer and activator of transcription 3 (STAT-3) but not Akt is essential, whereas ischaemic cardiac preconditioning (IPC) requires both STAT-3 and Akt at the time of reperfusion. However, it is not known whether the same signalling pattern occurs during the preconditioning stimulus (trigger phase) and whether links exist between STAT-3 and Akt. Hence, our hypothesis is that concomitant activation or co-interaction between these two key signals is required during the trigger phase for IPC. Conversely, we proposed that there would be no such interaction when preconditioning was induced by TNF (TNF-PC).
Methods: Cardiomyocytes, isolated from adult wild-type (WT) and cardiac-specific STAT-3 knockout (KO) mice, were exposed to simulated ischaemia-reperfusion. Cells were preconditioned either by 30 min simulated ischaemia or by 30 min TNF (0.5 ng/ml) in the presence or absence of AG490 (100 nM) or wortmannin (100 nM) to inhibit STAT-3 or Akt, respectively. Cell viability was evaluated by trypan blue and phosphorylation levels of STAT-3, and Akt were measured by Western blot analysis. Similar experiments were conducted in isolated rat heart subjected to an ischaemia-reperfusion insult.
Results: Both preconditioning stimuli failed to protect KO cardiomyocytes, and addition of AG490 abolished preconditioning in WT cardiomyocytes or isolated hearts. While wortmannin abolished the protection afforded by IPC, it did not affect TNF-PC in both models. Western blot analysis demonstrated that added wortmannin during IPC stimulus decreased STAT-3 phosphorylation while, conversely, AG490 reduced Akt phosphorylation.
Conclusion: STAT-3 activation could be achieved independently of Akt during TNF-PC. In contrast, during an IPC stimulus, both prosurvival signalling molecule cascades acted in concert so that inhibiting activation of STAT-3 also inhibited that of Akt, and vice-versa.
Time for primary review: 21 days
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