Akt or phosphoinositide-3-kinase inhibition reverses cardio-protection in Toll-like receptor 2 deficient mice.

Jan Mersmann, Nguyen Tran, Kathrina Latsch, Katharina Habeck, Franziska Iskandar, René Zimmermann, Kai Zacharowski

Clinic of Anaesthesiology, Intensive Care Medicine, and Pain Therapy, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.

Resuscitation 2012 Nov

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Absence or inhibition of Toll-like receptor 2 (TLR2) signalling during murine myocardial ischaemia/reperfusion (MI/R) decreases myocardial necrosis and inflammation, thereby ameliorating cardiac dysfunction and improving survival. In the present study, we provide evidence for the involvement of the phosphoinositide-3-kinase/Akt pathway in TLR2-dependent reperfusion injury. Adult male wild-type (WT) and TLR2(-/-) mice were subjected to myocardial ischaemia (30min) and reperfusion (4h). Animals were treated with phosphoinositide-3-kinase inhibitor wortmannin, Akt inhibitor V (triciribine), or vehicle 1h prior to MI/R. Protein expression levels of Akt1 and phosphoinositide-3-kinase and their respective phosphorylated forms were determined by Western blot analysis. Myocardial necrosis was quantified after staining with the tetrazolium method and by troponin T plasma levels. TLR2(-/-) mice displayed significantly increased Akt and phospho-Akt levels compared to WT mice, whilst no significant difference in phosphoinositide-3-kinase expression and phosphorylation could be observed. TLR2(-/-) mice also showed a blunted myocardial necrosis, the extent of which inversely correlated with Akt expression and degree of phosphorylation. Pharmacological inhibition of both, phosphoinositide-3-kinase or Akt, reversed the cardioprotection observed in TLR2(-/-) mice, whilst no effect could be observed in WT mice. Akt is an important mediator of cardioprotection in TLR2(-/-) animals during MI/R. The effect is, however, likely mediated by its genomic overexpression in the heart of TLR2(-/-) animals whilst Akt activation by phosphoinositide-3-kinase is unaltered. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Citation

Jan Mersmann, Nguyen Tran, Kathrina Latsch, Katharina Habeck, Franziska Iskandar, René Zimmermann, Kai Zacharowski. Akt or phosphoinositide-3-kinase inhibition reverses cardio-protection in Toll-like receptor 2 deficient mice. Resuscitation. 2012 Nov;83(11):1404-10