title: TLR2 ligands attenuate cardiac dysfunction in polymicrobial sepsis via a phosphoinositide 3-kinase-dependent mechanism.
abstract: Myocardial dysfunction is a major consequence of septic shock and contributes to the high mortality of sepsis. In the present study, we examined the effect of Toll-like receptor 2 (TLR2) ligands, peptidoglycan (PGN), and Pam3CSK4 (Pam3) on cardiac function in cecal ligation and puncture (CLP)-induced sepsis in mice. We also investigated whether the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is involved in the effect of TLR2 ligands on cardiac function in CLP mice. PGN was administered to C57B6/L mice 1 h before the induction of CLP. Sham surgically operated mice served as a control. Cardiac function indexes (rate of change in left ventricular pressure, stroke work, cardiac output, and ejection fraction) were examined by a microconductance pressure catheter. Cardiac function was significantly decreased 6 h after CLP-induced sepsis compared with sham-operated control. In contrast, PGN administration attenuated CLP-induced cardiac dysfunction. Importantly, the therapeutic treatment with Pam3 1 h after CLP also significantly attenuated cardiac dysfunction in CLP mice. However, the beneficial effect of TLR2 ligands on cardiac dysfunction in CLP-mice was abolished in TLR2-deficient mice. PGN administration significantly increased the levels of phospho-Akt and phospho-GSK-3beta in the myocardium compared with the levels in untreated CLP mice. PI3K inhibition abolished the PGN-induced attenuation of cardiac dysfunction in CLP mice. In conclusion, these data demonstrate that the administration of TLR2 ligands, PGN, or Pam3 attenuates cardiac dysfunction in septic mice via a TLR2/PI3K-dependent mechanism. More significantly, Pam3 therapeutic treatment will have a potential clinical relevance.
authors.affiliation: Dept. of Surgery, East Tennessee State Univ., Johnson City, TN 37614-0575, USA.
authors.forename: Tuanzhu
authors.initials: T
authors.lastname: Ha
authors.forename: Chen
authors.initials: C
authors.lastname: Lu
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Fang
authors.initials: F
authors.lastname: Hua
authors.forename: Yulong
authors.initials: Y
authors.lastname: Hu
authors.forename: Jim
authors.initials: J
authors.lastname: Kelley
authors.forename: Krishna
authors.initials: K
authors.lastname: Singh
authors.forename: Race L
authors.initials: RL
authors.lastname: Kao
authors.forename: John
authors.initials: J
authors.lastname: Kalbfleisch
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Chuanfu
authors.initials: C
authors.lastname: Li
mesh_terms: D000818:Animals; D002302:Cardiac Output / Q000502:physiology; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006321:Heart / Q000503:physiopathology; D006331:Heart Diseases / Q000188:drug therapy* / Q000503:physiopathology; D008024:Ligands; D055666:Lipopeptides / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010457:Peptidoglycan / Q000627:therapeutic use*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D018805:Sepsis / Q000188:drug therapy* / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D013318:Stroke Volume / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000502:physiology*
chemical_list: D008024:Ligands; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D010457:Peptidoglycan; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3