title: Lipopolysaccharide-induced myocardial protection against ischaemia/reperfusion injury is mediated through a PI3K/Akt-dependent mechanism.
abstract: OBJECTIVE
  The ability of lipopolysaccharide (LPS) pre-treatment to induce cardioprotection following ischaemia/reperfusion (I/R) has been well documented; however, the mechanisms have not been fully elucidated. LPS is a Toll-like receptor 4 (TLR4) ligand. Recent evidence indicates that there is cross-talk between the TLR and phosphoinositide 3-kinase/Akt (PI3K/Akt) signalling pathways. We hypothesized that activation of PI3K/Akt signalling plays a critical role in LPS-induced cardioprotection.
  
  
  RESULTS
  To evaluate this hypothesis, we pre-treated mice with LPS 24 h before the hearts were subjected to ischaemia (45 min) and reperfusion (4 h). We examined activation of the PI3K/Akt/GSK-3beta signalling pathway. The effect of PI3K/Akt inhibition on LPS-induced cardioprotection was also evaluated. LPS pre-treatment significantly reduced infarct size (71.25%) compared with the untreated group (9.3+/-1.58 vs. 32.3+/-2.92%, P<0.01). Cardiac myocyte apoptosis and caspase-3 activity in LPS-pre-treated mice were significantly reduced following I/R. LPS pre-treatment significantly increased the levels of phospho-Akt, phospho-GSK-3beta, and heat shock protein 27 in the myocardium. Pharmacological inhibition of PI3K by LY294002 or genetic modulation employing kinase-defective Akt transgenic mice abolished the cardioprotection induced by LPS.
  
  
  CONCLUSIONS
  These results indicate that LPS-induced cardioprotection in I/R injury is mediated through a PI3K/Akt-dependent mechanism.
authors.affiliation: Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, PO Box 70575, TN 37614-0575, USA.
authors.forename: Tuanzhu
authors.initials: T
authors.lastname: Ha
authors.forename: Fang
authors.initials: F
authors.lastname: Hua
authors.forename: Xiang
authors.initials: X
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Julie R
authors.initials: JR
authors.lastname: McMullen
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shioi
authors.forename: Seigo
authors.initials: S
authors.lastname: Izumo
authors.forename: Jim
authors.initials: J
authors.lastname: Kelley
authors.forename: Xiag
authors.initials: X
authors.lastname: Gao
authors.forename: William
authors.initials: W
authors.lastname: Browder
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
authors.forename: Race L
authors.initials: RL
authors.lastname: Kao
authors.forename: Chuanfu
authors.initials: C
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D053148:Caspase 3; D002867:Chromones; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008070:Lipopolysaccharides; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C486699:Hspb2 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C000605507:Gsk3b protein, mouse; C505409:Casp3 protein, mouse