title: Bacterial DNA induces myocardial inflammation and reduces cardiomyocyte contractility: role of toll-like receptor 9.
abstract: OBJECTIVE
  Myocardial function is severely compromised during sepsis. Several underlying mechanisms have been proposed. The innate immune system, i.e. toll-like receptor (TLR) 2 and 4, significantly contributes to cardiac dysfunction. Little is known regarding TLR9 and its pathogenic ligand bacterial DNA in the myocardium. We therefore studied the role of TLR9 in myocardial inflammation and cardiac contractility.
  
  
  RESULTS
  Wild-type (WT, C57BL/6) and TLR9-deficient (TLR9-D) mice and isolated cardiomyocytes were challenged with synthetic bacterial DNA (CpG-ODN). Myocardial contractility as well as markers of inflammation/signalling were determined. Isolated cardiomyocytes incorporated fluorescence-marked CpG-ODN. In WT mice, CpG-ODN caused a robust response in hearts demonstrated by increased levels of tumour necrosis factor (TNF-alpha), interleukin (IL)-1beta, IL-6, inducible nitric oxide synthase (iNOS), and nuclear factor kappaB activity. This inflammatory response was absent in TLR9-D mice. Under similar conditions, contractility measurements of isolated ventricular cardiomyocytes demonstrated a TLR9-dependent loss of sarcomeric shortening after CpG-ODN exposure. This observation was iNOS dependent as the application of a specific iNOS inhibitor reversed sarcomeric shortening to normal levels.
  
  
  CONCLUSIONS
  Our data suggest that bacterial DNA contributes to myocardial cytokine production and loss of cardiomyocyte contractility via TLR9.
authors.affiliation: Department for Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Sigmund-Freud-Strasse 25, Bonn 53105, Germany. pascal.knuefermann@ukb.uni-bonn.de
authors.forename: Pascal
authors.initials: P
authors.lastname: Knuefermann
authors.forename: Markus
authors.initials: M
authors.lastname: Schwederski
authors.forename: Markus
authors.initials: M
authors.lastname: Velten
authors.forename: Peter
authors.initials: P
authors.lastname: Krings
authors.forename: Heidi
authors.initials: H
authors.lastname: Ehrentraut
authors.forename: Myriam
authors.initials: M
authors.lastname: Rüdiger
authors.forename: Olaf
authors.initials: O
authors.lastname: Boehm
authors.forename: Klaus
authors.initials: K
authors.lastname: Fink
authors.forename: Ulrike
authors.initials: U
authors.lastname: Dreiner
authors.forename: Christian
authors.initials: C
authors.lastname: Grohé
authors.forename: Andreas
authors.initials: A
authors.lastname: Hoeft
authors.forename: Georg
authors.initials: G
authors.lastname: Baumgarten
authors.forename: Alexander
authors.initials: A
authors.lastname: Koch
authors.forename: Kai
authors.initials: K
authors.lastname: Zacharowski
authors.forename: Rainer
authors.initials: R
authors.lastname: Meyer
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D004269:DNA, Bacterial; D004195:Disease Models, Animal; D007113:Immunity, Innate; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009205:Myocarditis / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger / Q000378:metabolism; D012518:Sarcomeres / Q000201:enzymology; D018805:Sepsis / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000503:physiopathology; D013997:Time Factors; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C408982:CPG-oligonucleotide; D016207:Cytokines; D004269:DNA, Bacterial; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse