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.

Abstract

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.

• Authors: Ming Gao, Tuanzhu Ha, Xia Zhang, Xiaohui Wang, Li Liu, John Kalbfleisch, Krishna Singh, David Williams, Chuanfu Li
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 207 Issue 9 Pg. 1471-9 (May 01 2013) ISSN: 1537-6613 [Electronic] United States
• PMID: 23359590 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• CPG-oligonucleotide
• Cardiovascular Agents
• Oligodeoxyribonucleotides

Topics

• Animals
• Cardiovascular Agents (administration & dosage)
• Echocardiography
• Heart (drug effects, physiopathology)
• Heart Failure (prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Oligodeoxyribonucleotides (administration & dosage)
• Sepsis (complications, drug therapy)
• Treatment Outcome