title: The Toll-like receptor 9 ligand CPG-C attenuates acute inflammatory cardiac dysfunction.
abstract: Stimulation of toll-like receptor 9 (TLR9) by CpG-C containing oligonucleotides attenuates ischemic injury in the brain and liver. In this study, we investigate whether any of the three classes of CpG (A, B, or C) mitigate ischemia-induced cardiac dysfunction. We measured left ventricular ejection fraction (LVEF) in C57BL/6 mice using transthoracic echocardiography. Using LPS as an inflammatory stimulus, CpG-C was uniquely able to prevent cardiac dysfunction; its activity was confirmed through nuclear factor κB transcriptional activity assay in HL-1 cardiomyocytes. We went on to investigate CpG-C's efficacy and mechanism in the treatment of ischemia-reperfusion. Compared with baseline, no class of CpG significantly altered LVEF at 6 or 24 h; 40 mg/kg LPS induced a rapid, profound suppression of LVEF compared with baseline (26% ± 1.4% vs. 65% ± 1.4%), whereas pretreatment with CpG demonstrated that of the three classes, only CpG-C prevented the LPS -induced decrease in LVEF (51% ± 5.8%). In separate mice, 1-h ischemia followed by reperfusion of the left anterior descending artery resulted in a 7-day suppression of the LVEF (66% ± 5.2% at baseline; 46% ± 4.7% at day 1, and 46% ± 4.0% at day 7), whereas mice either pretreated with or begun on an infusion of CpG-C during the ischemia had no significant decline in LVEF. Gene expression microarray of CpG-C-stimulated cells revealed upregulation of the nuclear factor κB pathway inhibitors TNFAIP3, NFKBIA, TRIM30, and TNIP1. These may play a role in attenuation of cardiac inflammation. The TLR9 ligand CpG-C attenuates the acute inflammatory cardiac dysfunction induced by both LPS and ischemia-reperfusion of the left anterior descending artery.
authors.affiliation: Critical Care Research Laboratories, Heart + Lung Institute, St Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Sumeet
authors.initials: S
authors.lastname: Mathur
authors.forename: Keith R
authors.initials: KR
authors.lastname: Walley
authors.forename: John H
authors.initials: JH
authors.lastname: Boyd
mesh_terms: D000818:Animals; D004452:Echocardiography; D007249:Inflammation / Q000188:drug therapy*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use*; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000378:metabolism*
chemical_list: C527702:CpG ODN 2395; C513200:CpG-A 2336; C513201:CpG-B 2006; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9