Tumour necrosis factor-alpha contributes to improved cardiac ischaemic tolerance in rats adapted to chronic continuous hypoxia
Abstrakt
AimIt has been demonstrated that tumour necrosis factor-alpha (TNF-) via its receptor 2 (TNFR2) plays a role in the cardioprotective effects of preconditioning. It is also well known that chronic hypoxia is associated with activation of inflammatory response.
With this background, we hypothesized that TNF- signalling may contribute to the improved ischaemic tolerance of chronically hypoxic hearts. MethodsAdult male Wistar rats were kept either at room air (normoxic controls) or at continuous normobaric hypoxia (CNH; inspired O-2 fraction 0.1) for 3weeks; subgroups of animals were treated with infliximab (monoclonal antibody against TNF-; 5mgkg(-1), i.p., once a week).
Myocardial levels of oxidative stress markers and the expression of selected signalling molecules were analysed. Infarct size (tetrazolium staining) was assessed in open-chest rats subjected to acute coronary artery occlusion/reperfusion.
ResultsCNH increased myocardial TNF- level and expression of TNFR2; this response was abolished by infliximab treatment. CNH reduced myocardial infarct size from 50.84.3% of the area at risk in normoxic animals to 35.5 +/- 2.4%.
Infliximab abolished the protective effect of CNH (44.9 +/- 2.0%). CNH increased the levels of oxidative stress markers (3-nitrotyrosine and malondialdehyde), the expression of nuclear factor B and manganese superoxide dismutase, while these effects were absent in infliximab-treated animals.
CNH-elevated levels of inducible nitric oxide synthase and cyclooxygenase 2 were not affected by infliximab. ConclusionTNF- plays a role in the induction of ischaemia-resistant cardiac phenotype of CNH rats, possibly via the activation of protective redox signalling.