CpG-ODN, the TLR9 agonist, attenuates myocardial ischemia/reperfusion injury: involving activation of PI3K/Akt signaling.
BACKGROUND
Toll-like receptors (TLRs) have been implicated in myocardial ischemia/reperfusion (I/R) injury. The TLR9 ligand, CpG-ODN has been reported to improve cell survival. We examined effect of CpG-ODN on myocardial I/R injury.


METHODS
Male C57BL/6 mice were treated with either CpG-ODN, control-ODN, or inhibitory CpG-ODN (iCpG-ODN) 1h prior to myocardial ischemia (60min) followed by reperfusion. Untreated mice served as I/R control (n=10/each group). Infarct size was determined by TTC straining. Cardiac function was examined by echocardiography before and after myocardial I/R up to 14days.


RESULTS
CpG-ODN administration significantly decreased infarct size by 31.4% and improved cardiac function after myocardial I/R up to 14days. Neither control-ODN nor iCpG-ODN altered I/R-induced myocardial infarction and cardiac dysfunction. CpG-ODN attenuated I/R-induced myocardial apoptosis and prevented I/R-induced decrease in Bcl2 and increase in Bax levels in the myocardium. CpG-ODN increased Akt and GSK-3β phosphorylation in the myocardium. In vitro data suggested that CpG-ODN treatment induced TLR9 tyrosine phosphorylation and promoted an association between TLR9 and the p85 subunit of PI3K. Importantly, PI3K/Akt inhibition and Akt kinase deficiency abolished CpG-ODN-induced cardioprotection.


CONCLUSIONS
CpG-ODN, the TLR9 ligand, induces protection against myocardial I/R injury. The mechanisms involve activation of the PI3K/Akt signaling pathway.
Department of Surgery, East Tennessee State University, Johnson City, TN 37614, USA.
Zhijuan
Z
Cao
Danyang
D
Ren
Tuanzhu
T
Ha
Li
L
Liu
Xiaohui
X
Wang
John
J
Kalbfleisch
Xiang
X
Gao
Race
R
Kao
David
D
Williams
Chuanfu
C
Li
D000818:Animals; D002460:Cell Line; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism / Q000601:surgery*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051217:Toll-Like Receptor 9 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt