title: The toll-like receptor 9 agonist, CpG-oligodeoxynucleotide 1826, ameliorates cardiac dysfunction after trauma-hemorrhage.
abstract: Cardiovascular collapse is the major factor contributing to the mortality of trauma-hemorrhage (T-H) patients. Toll-like receptors (TLRs) play a critical role in T-H-induced cardiac dysfunction. This study evaluated the role of TLR9 agonist, CpG-oligodeoxynucleotide (ODN) 1826, in cardiac functional recovery after T-H. Trauma-hemorrhage was induced in a murine model by soft tissue injury and blood withdrawals from the jugular vein to a mean arterial pressure of 35 ± 5 mmHg. Mice were treated with CpG-ODN 1826 (10 μg/30 g body weight) by intraperitoneal injection 1 h before T-H (n = 5-8/group). Hemodynamic parameters were measured before, during hemorrhage, and at 60 min after T-H. Trauma-hemorrhage significantly decreased the mean arterial pressure and left ventricular pressure compared with sham controls. In contrast, CpG-ODN administration significantly attenuated the decrease in arterial pressure and left ventricular pressure due to T-H. Trauma-hemorrhage markedly decreased myocardial levels of phosphorylated Akt by 57.9%. However, CpG-ODN treatment significantly blunted the decrement in phospho-Akt by activating the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. The PI3K inhibitor LY294002 partially abolished CpG-induced cardioprotection, indicating that additional signaling pathways are involved in the protective effect of CpG-ODN after T-H. We observed that CpG-ODN treatment also significantly attenuated the decrease in myocardial phospho-ERK levels after T-H. Inhibition of ERK by U0126 also partially abolished the cardioprotective effect of CpG-ODN after T-H. Our data suggest that CpG-ODN significantly attenuates T-H-induced cardiac dysfunction. The mechanisms involve activation of both PI3K/Akt and ERK signaling pathways. The TLR9 agonist, CpG-ODN 1826, may provide a novel treatment strategy for preventing or managing cardiac dysfunction and enhancing recovery in T-H patients.
authors.affiliation: Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City 37614, Tennessee, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.forename: Ming
authors.initials: M
authors.lastname: Gao
authors.forename: Tuanzhu
authors.initials: T
authors.lastname: Ha
authors.forename: John H
authors.initials: JH
authors.lastname: Kalbfleisch
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
authors.forename: Chuanfu
authors.initials: C
authors.lastname: Li
authors.forename: Race L
authors.initials: RL
authors.lastname: Kao
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006331:Heart Diseases / Q000517:prevention & control*; D006470:Hemorrhage / Q000150:complications*; D007022:Hypotension / Q000517:prevention & control*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017695:Soft Tissue Injuries / Q000150:complications*; D051217:Toll-Like Receptor 9 / Q000819:agonists*
chemical_list: D000276:Adjuvants, Immunologic; D002867:Chromones; C423449:CpG ODN 1826; D004791:Enzyme Inhibitors; D009025:Morpholines; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt