The Toll-like receptor 9 ligand, CpG oligodeoxynucleotide, attenuates cardiac dysfunction in polymicrobial sepsis, involving activation of both phosphoinositide 3 kinase/Akt and extracellular-signal-related kinase signaling.
BACKGROUND
Toll-like receptors (TLRs) play a role in the pathophysiology of sepsis and multiple organ failure. This study examined the effect of CpG oligodeoxynucleotide (CpG-ODN), the TLR9 ligand, on polymicrobial sepsis-induced cardiac dysfunction.


METHODS
Male C57BL/6 mice were treated with CpG-ODN, control CpG-ODN (control-ODN), or inhibitory CpG-ODN (iCpG-ODN) 1 hour prior to cecal ligation and puncture (CLP)-induced sepsis. Mice that underwent sham surgery served as sham controls. Cardiac function was examined by echocardiography before and 6 hours after CLP.


RESULTS
Cardiac function was significantly decreased 6 hours after CLP. CpG-ODN prevented CLP-induced cardiac dysfunction, as evidenced by maintenance of the ejection fraction and fractional shortening. Control-ODN or iCpG-ODN did not alter CLP-induced cardiac dysfunction. CpG-ODN significantly attenuated CLP-induced myocardial apoptosis and increased myocardial Akt and extracellular-signal-related kinase (ERK) phosphorylation levels following CLP. In vitro experiments demonstrated that CpG-ODN promotes an association between TLR9 and Ras, resulting in Akt and ERK phosphorylation. Inhibition of phosphoinositide 3-kinase (PI3K) by Ly294002 or inhibition of ERK by U0126 in vivo abolished CpG-ODN attenuation of CLP-induced cardiac dysfunction.


CONCLUSIONS
CpG-ODN prevents CLP-induced cardiac dysfunction, in part through activation of PI3K/Akt and ERK signaling. Modulation of TLR9 could be an effective approach for treatment of cardiovascular dysfunction in patients with sepsis or septic shock.
Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614-0575, USA.
Ming
M
Gao
Tuanzhu
T
Ha
Xia
X
Zhang
Xiaohui
X
Wang
Li
L
Liu
John
J
Kalbfleisch
Krishna
K
Singh
David
D
Williams
Chuanfu
C
Li
D000818:Animals; D002317:Cardiovascular Agents / Q000008:administration & dosage*; D004452:Echocardiography; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D006333:Heart Failure / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D018805:Sepsis / Q000150:complications* / Q000188:drug therapy*; D016896:Treatment Outcome
C408982:CPG-oligonucleotide; D002317:Cardiovascular Agents; D009838:Oligodeoxyribonucleotides