title: TNFalpha is required to confer protection in an in vivo model of classical ischaemic preconditioning.
abstract: Although Tumor Necrosis Factor alpha (TNFalpha) is used as a preconditioning mimetic in vitro, its role in ischaemic preconditioning (IPC) has not been clearly defined. Here, we propose to use an in vivo model (that takes into account the activation of leukocytes which may affect levels of TNFalpha) to demonstrate that i) TNFalpha acts as a trigger in IPC and ii) the dose-dependent nature of this cardioprotective effect of TNFalpha. Male Wistar rats were subjected to 30 min of left coronary artery occlusion (index ischaemia), followed by 24 h reperfusion. In the presence or absence of a soluble TNFalpha receptor (sTNFalpha-R), preconditioning was induced by 3 cycles of ischaemia (3 min)/reperfusion (5 min) (IPC) or various doses (0.05-4 microg/kg) of exogenous TNFalpha. Following 24 h reperfusion, infarct size (IS, expressed as % of the area at risk (AAR)) was assessed. Tissue levels of TNFalpha from the AAR, following IPC and TNFalpha stimulus were determined using Western Blot. IPC caused decrease in IS (4.5+/-1.3% vs 30.8+/-4.3% in ischaemic rats; P<0.001) and increase of TNFalpha levels following the IPC stimulus. The protective effect of IPC was abrogated in the presence of the sTNFalpha-R. In addition, exogenous TNFalpha dose-dependently reduced IS with maximal protection at a dose of 0.1 microg/kg (IS=12.6%, P<0.01 vs ischaemic). In conclusion our data provide strong evidence for a role of TNFalpha during the trigger phase of IPC. In addition, exogenous TNFalpha mimics IPC by providing a dose-dependent cardioprotective effect against ischaemia-reperfusion injury in vivo.
authors.affiliation: Hatter Institute for Cardiology Research, Department of Medicine, Cape Heart Centre, Faculty of Health Sciences, University of Cape Town, Observatory 7925, South Africa. gdeuchar@staffmail.ed.ac.uk
authors.forename: Graeme A
authors.initials: GA
authors.lastname: Deuchar
authors.forename: Lionel H
authors.initials: LH
authors.lastname: Opie
authors.forename: Sandrine
authors.initials: S
authors.lastname: Lecour
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D018124:Receptors, Tumor Necrosis Factor; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha