title: Sustained Toll-Like Receptor 9 Activation Promotes Systemic and Cardiac Inflammation, and Aggravates Diastolic Heart Failure in SERCA2a KO Mice.
abstract: OBJECTIVE
  Cardiac inflammation is important in the pathogenesis of heart failure. However, the consequence of systemic inflammation on concomitant established heart failure, and in particular diastolic heart failure, is less explored. Here we investigated the impact of systemic inflammation, caused by sustained Toll-like receptor 9 activation, on established diastolic heart failure.
  
  
  RESULTS
  Diastolic heart failure was established in 8-10 week old cardiomyocyte specific, inducible SERCA2a knock out (i.e., SERCA2a KO) C57Bl/6J mice. Four weeks after conditional KO, mice were randomized to receive Toll-like receptor 9 agonist (CpG B; 2μg/g body weight) or PBS every third day. After additional four weeks, echocardiography, phase contrast magnetic resonance imaging, histology, flow cytometry, and cardiac RNA analyses were performed. A subgroup was followed, registering morbidity and death. Non-heart failure control groups treated with CpG B or PBS served as controls. Our main findings were: (i) Toll-like receptor 9 activation (CpG B) reduced life expectancy in SERCA2a KO mice compared to PBS treated SERCA2a KO mice. (ii) Diastolic function was lower in SERCA2a KO mice with Toll-like receptor 9 activation. (iii) Toll-like receptor 9 stimulated SERCA2a KO mice also had increased cardiac and systemic inflammation.
  
  
  CONCLUSIONS
  Sustained activation of Toll-like receptor 9 causes cardiac and systemic inflammation, and deterioration of SERCA2a depletion-mediated diastolic heart failure.
authors.affiliation: Research Institute of Internal medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Center for Heart failure Research, University of Oslo, Oslo, Norway; K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway.
authors.forename: Yangchen
authors.initials: Y
authors.lastname: Dhondup
authors.affiliation: Center for Heart failure Research, University of Oslo, Oslo, Norway; Institute for Experimental Medical Research, Oslo University Hospital, Ullevaal, Oslo, Norway.
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.affiliation: K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway; Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Helge
authors.initials: H
authors.lastname: Scott
authors.affiliation: Research Institute of Internal medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Center for Heart failure Research, University of Oslo, Oslo, Norway; K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Sandanger
authors.affiliation: Center for Heart failure Research, University of Oslo, Oslo, Norway; Institute for Experimental Medical Research, Oslo University Hospital, Ullevaal, Oslo, Norway.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Center for Heart failure Research, University of Oslo, Oslo, Norway; Institute for Experimental Medical Research, Oslo University Hospital, Ullevaal, Oslo, Norway.
authors.forename: Solveig Bjærum
authors.initials: SB
authors.lastname: Haugstad
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital, Ullevaal, Oslo, Norway; Bjørknes college, Oslo, Norway.
authors.forename: Jan Magnus
authors.initials: JM
authors.lastname: Aronsen
authors.affiliation: Research Institute of Internal medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway.
authors.forename: Trine
authors.initials: T
authors.lastname: Ranheim
authors.affiliation: Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Centre for Imported and Tropical Diseases, Department of Infectious Diseases, Oslo University Hospital, Ulleval, Oslo, Norway.
authors.forename: Sigve Dhondup
authors.initials: SD
authors.lastname: Holmen
authors.affiliation: Research Institute of Internal medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway.
authors.forename: Katrine
authors.initials: K
authors.lastname: Alfsnes
authors.affiliation: K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway; Institute for Surgical Research, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Muhammad Shakil
authors.initials: MS
authors.lastname: Ahmed
authors.affiliation: K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Institute for Surgical Research, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Håvard
authors.initials: H
authors.lastname: Attramadal
authors.affiliation: Center for Heart failure Research, University of Oslo, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Gullestad
authors.affiliation: Research Institute of Internal medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.affiliation: Center for Heart failure Research, University of Oslo, Oslo, Norway; Institute for Experimental Medical Research, Oslo University Hospital, Ullevaal, Oslo, Norway.
authors.forename: Geir
authors.initials: G
authors.lastname: Christensen
authors.affiliation: Research Institute of Internal medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Center for Heart failure Research, University of Oslo, Oslo, Norway; K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Arne
authors.initials: A
authors.lastname: Yndestad
authors.affiliation: Research Institute of Internal medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Center for Heart failure Research, University of Oslo, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Department of Internal Medicine, Diakonhjemmet Hospital, Oslo, Norway.
authors.forename: Leif Erik
authors.initials: LE
authors.lastname: Vinge
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D003971:Diastole; D005355:Fibrosis; D005786:Gene Expression Regulation; D054144:Heart Failure, Diastolic / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006909:Hydroxyproline / Q000378:metabolism; D007249:Inflammation / Q000150:complications / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061213:Mortality, Premature; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology*; D009929:Organ Size; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000172:deficiency* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D014463:Ultrasonography
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; D012333:RNA, Messenger; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse; D006909:Hydroxyproline