title: Postconditioning with a CpG containing oligodeoxynucleotide ameliorates myocardial infarction in a murine closed-chest model.
abstract: OBJECTIVE
  Toll-like receptor (TLR)9 ligand CpG-oligodeoxynucleotide (CpG-ODN) exerts preconditioning in myocardial ischemia/reperfusion. We hypothesized a postconditioning effect of CpG-ODN in a murine closed-chest model of myocardial infarction.
  
  
  METHODS
  C57BL/6 (12 weeks, male, WT) mice were instrumented at the left anterior descending artery, then allowed 5d of recovery before 30 min ischemia. Treatments comprised: 1) PBS: 250 μl phosphate buffer solution intraperitoneally 5 min before reperfusion and 2) IPC (ischemic postconditioning): 3 twenty-second reperfusion and occlusion episodes at the end of ischemia 3) CpG-ODN: 1668 thioate 0.2 μmol/kg BW intraperitoneally 5 min before reperfusion. Infarct size was assessed via triphenyltetrazolium chloride (TTC) staining after 2 and 24h reperfusion. Myocardial mRNA-expression of cytokines was measured using real-time PCR after 2h reperfusion. Phosphatidylinositol-3 kinase (PI3K)-inhibitor wortmannin was injected intraperitoneally in WT 15 min before postconditioning and PBS in each group. Cardiac function in WT was assessed with a left-ventricular pressure-volume catheter at 24h reperfusion.
  
  
  RESULTS
  Following 30 min ischemia and 2h reperfusion, infarct size was diminished by 90% in WT postconditioned with CpG-ODN (2.4 ± 1.55 IS/AAR%) and IPC (1.98 ± 1.03 IS/AAR%) compared to PBS mice (23.2 ± 3.97 IS/AAR%). Infarct size increased following 24h reperfusion but the differences remained robust. Expression of TNF-α and IL-10 was increased in CpG-ODN. Wortmannin abolished the postconditioning effect of CpG-ODN and IPC. Ejection fraction and preload-recruitable stroke work were significantly greater in CpG-ODN mice.
  
  
  CONCLUSIONS
  CpG-ODN confers postconditioning via activation of TLR9. Cardiac function is preserved following CpG-ODN postconditioning. The PI3K -inhibitor wortmannin attenuates CpG-ODN postconditioning.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University of Bonn, Sigmund-Freud-Str. 25, D-53115 Bonn, Germany. Electronic address: Se-Chan.Kim@ukb.uni-bonn.de.
authors.forename: Se-Chan
authors.initials: SC
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University of Bonn, Sigmund-Freud-Str. 25, D-53115 Bonn, Germany; Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Shuijing
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Xiangming
authors.initials: X
authors.lastname: Fang
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University of Bonn, Sigmund-Freud-Str. 25, D-53115 Bonn, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Neumann
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University of Bonn, Sigmund-Freud-Str. 25, D-53115 Bonn, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Eichhorn
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University of Bonn, Sigmund-Freud-Str. 25, D-53115 Bonn, Germany.
authors.forename: Grigorij
authors.initials: G
authors.lastname: Schleifer
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University of Bonn, Sigmund-Freud-Str. 25, D-53115 Bonn, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Boehm
authors.affiliation: Institute of Physiology, University of Bonn, Nussallee 11, D-53115 Bonn, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Meyer
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University of Bonn, Sigmund-Freud-Str. 25, D-53115 Bonn, Germany.
authors.forename: Stilla
authors.initials: S
authors.lastname: Frede
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University of Bonn, Sigmund-Freud-Str. 25, D-53115 Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hoeft
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University of Bonn, Sigmund-Freud-Str. 25, D-53115 Bonn, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Baumgarten
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University of Bonn, Sigmund-Freud-Str. 25, D-53115 Bonn, Germany.
authors.forename: Pascal
authors.initials: P
authors.lastname: Knuefermann
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D007113:Immunity, Innate / Q000187:drug effects; D057775:Ischemic Postconditioning / Q000379:methods*; D008297:Male; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use*; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D009838:Oligodeoxyribonucleotides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D051217:Toll-Like Receptor 9; C408982:CPG-oligonucleotide; C495370:Tlr9 protein, mouse
keywords: Toll-like receptor; cytokines; innate immunity; myocardial infarction; postconditioning