TLR2 ligands attenuate cardiac dysfunction in polymicrobial sepsis via a phosphoinositide 3-kinase-dependent mechanism.
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.
Ha
Tuanzhu
T
Dept. of Surgery, East Tennessee State Univ., Johnson City, TN 37614-0575, USA.
Lu
Chen
C
Liu
Li
L
Hua
Fang
F
Hu
Yulong
Y
Kelley
Jim
J
Singh
Krishna
K
Kao
Race L
RL
Kalbfleisch
John
J
Williams
David L
DL
Gao
Xiang
X
Li
Chuanfu
C
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*
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