Published online before print December 12, 2005, doi: 10.1161/CIRCULATIONAHA.105.581058
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(Circulation. 2005;112:3911-3918.)
© 2005 American Heart Association, Inc.
Molecular Cardiology |
Pharmacological Preconditioning With Tumor Necrosis Factor-
Activates Signal Transducer and Activator of Transcription-3 at Reperfusion Without Involving Classic Prosurvival Kinases (Akt and Extracellular Signal–Regulated Kinase)
From the Department of Medicine (S.L., N.S., G.A.D., S.S., L.L., L.H.O.), Hatter Institute for Cardiology Research, Cape Heart Centre and Medical Research Council Interuniveristy, Cape Heart Group, Faculty of Health Sciences, University of Cape Town, Cape Town, and the Department of Medical Physiology (B.H.), Faculty of Health Sciences, University of Stellenbosch, Stellenbosch, South Africa.
Correspondence to Dr Sandrine Lecour, Department of Medicine, Hatter Institute for Cardiology Research, Cape Heart Centre, Faculty of Health Sciences, University of Cape Town, 7925 Observatory, South Africa. E-mail Sandrine{at}capeheart.uct.ac.za
Received May 25, 2005; de novo received August 4, 2005; revision received October 5, 2005; accepted October 7, 2005.
Background— We previously reported that tumor necrosis-factor-
(TNF-) can mimic classic ischemic preconditioning (IPC) in a dose- and time-dependent manner. Because TNF- activates the signal transducer and activator of transcription-3 (STAT-3), we hypothesized that TNF-–induced preconditioning requires phosphorylation of STAT-3 rather than involving the classic prosurvival kinases, Akt and extracellular signal–regulated kinase (Erk) 1/2, during early reperfusion.
Methods and Results— Isolated, ischemic/reperfused rat hearts were preconditioned by either IPC or low-dose TNF- (0.5 ng/mL). Western blot analysis confirmed that IPC phosphorylated Akt and Erk 1/2 after 5 minutes of reperfusion (Akt increased by 34±6% and Erk, by 105±28% versus control; P<0.01). Phosphatidylinositol 3-kinase/Akt inhibition (wortmannin) or mitogen-activated protein kinase–Erk 1/2 kinase inhibition (PD-98059) during early reperfusion abolished the infarct-sparing effect of IPC. In contrast, TNF- preconditioning did not phosphorylate these kinases (Akt increased by 7±7% and Erk, by 17±14% versus control; P=NS). Neither wortmannin nor PD-98059 inhibited TNF-–mediated cardioprotection. However, TNF- and IPC both phosphorylated STAT-3 and the proapoptotic protein Bcl-2 antagonist of cell death (BAD) (STAT-3 increased by 58±17% with TNF- or by 68±12% with IPC; BAD increased by 75±8% with TNF- or by 205±20% with IPC; P<0.01 versus control), thereby activating the former and inactivating the latter. The STAT-3 inhibitor AG 490 abolished cardioprotection and BAD phosphorylation with both preconditioning stimuli.
Conclusions— Activation of the classic prosurvival kinases (Akt and Erk 1/2) is not essential for TNF-–induced preconditioning in the early reperfusion phase. We show the existence of an alternative protective pathway that involves STAT-3 activation specifically at reperfusion in response to both TNF- and classic IPC. This novel prosurvival pathway may have potential therapeutic significance.
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