title: Akt or phosphoinositide-3-kinase inhibition reverses cardio-protection in Toll-like receptor 2 deficient mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Clinic of Anaesthesiology, Intensive Care Medicine, and Pain Therapy, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Mersmann
authors.forename: Nguyen
authors.initials: N
authors.lastname: Tran
authors.forename: Kathrina
authors.initials: K
authors.lastname: Latsch
authors.forename: Katharina
authors.initials: K
authors.lastname: Habeck
authors.forename: Franziska
authors.initials: F
authors.lastname: Iskandar
authors.forename: René
authors.initials: R
authors.lastname: Zimmermann
authors.forename: Kai
authors.initials: K
authors.lastname: Zacharowski
mesh_terms: D000730:Androstadienes / Q000494:pharmacology*; D000818:Animals; D008297:Male; D051379:Mice; D017202:Myocardial Ischemia / Q000503:physiopathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000503:physiopathology; D012263:Ribonucleosides / Q000494:pharmacology*; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000502:physiology*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012263:Ribonucleosides; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C023764:triciribine; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin