© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Classic ischemic but not pharmacologic preconditioning is abrogated following genetic ablation of the TNF
gene
Hatter Institute for Cardiology Research, MRC Inter-University Cape Heart Group, University of Cape Town Medical School, Observatory 7925, Cape Town, South Africa
* Corresponding author. Tel.: +27-21-406-6350; fax: +27-21-447-8789 sack{at}capeheart.uct.ac.za
Objective: Tumor necrosis factor alpha (TNF
) is known to mimic ischemic preconditioning (IP). However, it is not known whether TNF-preconditioning is mediated by ‘established’ preconditioning signaling or via novel signaling cascades. Moreover, whether TNF is required to induce the ischemic preconditioning phenotype has not been determined. Methods: To evaluate the role of TNF, we determined the infarct-sparing effect of IP comparing TNF null (TNF–/–) and wild-type mice. The IP protocol included 4x5 min ischemia/reperfusion (I/R) prior to the index 35 min of global ischemia followed by 45 min of reperfusion in isolated perfused murine hearts. Infarct size was measured as a percentage of cardiac volume. To evoke particular signaling pathways numerous pharmacologic studies were performed. Results: Following IP, infarct size was significantly reduced by 43% in wild-type mice. In contrast, infarct size was not attenuated by IP in the TNF–/– group versus I/R controls (Infarct size—36±3%). Interestingly, pharmacologic preconditioning with adenosine (100 µM) and diazoxide (30 µM) mimicked IP in both the wild-type (infarct size—11±4% and 18±2%) and in TNF–/– mice (infarct size—15±4% and 23±3%) versus respective I/R controls. Recombinant TNF (0.5 ng/ml) administered for 7 min followed by a 10-min washout mimicked IP in wild-type mice but not in the TNF deficient mouse hearts. The cardioprotective effects of IP, adenosine and TNF were abolished by the co-administration of the putative mitochondrial KATP blocker 5-hydroxydecanoate. Conclusions: We demonstrate that cardiac TNF production is required for ischemic preconditioning-induced cardioprotection but not necessary in pharmacologic preconditioning with adenosine or diazoxide in TNF–/– mice. Moreover, TNF administration is sufficient to activate preconditioning in wild-type mice. Finally, as 5-hydroxydecanoate abrogates ischemic, adenosine and TNF induced preconditioning, this suggests that diverse signaling pathways converge at the level of mitochondrial KATP channel activation to mediate this cardioprotection.
KEYWORDS Adenosine; Immunology; Ischemia; K-ATP channel; Preconditioning
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