The use of moderate hypothermia during cardiac surgery is associated with repression of tumour necrosis factor-α via inhibition of activating protein-1: an experimental study

Ma Qing,Michael Wöltje,Jaime F Vazquez-Jimenez,Magdalena Sokalska,Kathrin Schumacher,Ralf Minkenberg,Marie-Christine Seghaye

doi:10.1186/cc4886

Abstract

IntroductionThe use of moderate hypothermia during experimental cardiac surgery is associated with decreased expression of tumour necrosis factor (TNF)-α in myocardium and with myocardial protection. In order to identify the cellular mechanisms that lead to that repression, we investigated the effect of hypothermia during cardiac surgery on both main signalling pathways involved in systemic inflammation, namely the nuclear factor-κB (NF-κB) and activating protein-1 pathways.MethodTwelve female pigs were randomly subjected to standardized cardiopulmonary bypass with moderate hypothermia or normothermia (temperature 28°C and 37°C, respectively; six pigs in each group). Myocardial probes were sampled from the right ventricle before, during and 6 hours after bypass. We detected mRNA encoding TNF-α by competitive RT-PCR and measured protein levels of TNF-α, inducible nitric oxide synthase and cyclo-oxygenase-2 by Western blotting. Finally, we assessed the activation of NF-κB and activating protein-1, as well as phosphorylation of p38 mitogen-activated protein kinase by electrophoretic mobility shift assay with super shift and/or Western blot.ResultsDuring and after cardiac surgery, animals subjected to hypothermia exhibited lower expression of TNF-α and cyclo-oxygenase-2 but not of inducible nitric oxide synthase. This was associated with lower activation of p38 mitogen-activated protein kinase and of its downstream effector activating protein-1 in hypothermic animals. In contrast, NF-κB activity was no different between groups.ConclusionThese findings indicate that the repression of TNF-α associated with moderate hypothermia during cardiac surgery is associated with inhibition of the mitogen-activated protein kinase p38/activating protein-1 pathway and not with inhibition of NF-κB. The use of moderate hypothermia during cardiac surgery may mitigate the perioperative systemic inflammatory response and its complications.

Highlights

The use of moderate hypothermia during experimental cardiac surgery is associated with decreased expression of tumour necrosis factor (TNF)-α in myocardium and with myocardial protection
During and after cardiac surgery, animals subjected to hypothermia exhibited lower expression of TNF-α and cyclooxygenase-2 but not of inducible nitric oxide synthase
These findings indicate that the repression of TNFα associated with moderate hypothermia during cardiac surgery is associated with inhibition of the mitogen-activated protein kinase p38/activating protein-1 pathway and not with inhibition of nuclear factor-κB (NF-κB)

Summary

Introduction

The use of moderate hypothermia during experimental cardiac surgery is associated with decreased expression of tumour necrosis factor (TNF)-α in myocardium and with myocardial protection. There is a large body of evidence that, in experimental models, over-expression of TNF-α in the myocardium is related to adverse cardiac effects such as postinfarct remodelling and ventricular dilatation [4], transition from hypertrophic to dilated cardiomyopathy due to apoptosis [5] and impaired postischaemic functional recovery [6]. AP = activating protein; COX = cyclo-oxygenase; CPB = cardiopulmonary bypass; IκB = NF-κB inhibitory protein; iNOS = inducible nitric oxide synthase; MAPK = mitogen-activated protein kinase; NF-κB = nuclear factor-κB; NO = nitric oxide; RT-PCR = reverse transcriptase polymerase chain reaction; TNF = tumour necrosis factor. In humans there is a clear relationship between TNF-α expression in the myocardium and the severity of dilated cardiomyopathy [9,10]

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