title: NLRP3 inflammasome activation during myocardial ischemia reperfusion is cardioprotective.
abstract: BACKGROUND
  The innate immune receptor NLRP3 recognizes tissue damage and initiates inflammatory processes through formation multiprotein complexes with the adaptor protein ASC and caspase-1, i.e. NLRP3 inflammasomes, which through cleavage of pro-IL-1β mediates release of bioactive IL-1β. We hypothesized that NLRP3 mediates tissue damage during acute myocardial infarction (MI) and sought to investigate the mechanisms herein in an experimental MI model in mice.
  
  
  RESULTS
  The left coronary artery (LCA) of WT, NLRP3(-/-) and ASC(-/-) mice of both genders was ligated for 30 min followed by 3 or 24 h reperfusion. For pre-conditioning studies, the TLR2 agonist Pam3CSK4 or PBS was injected intraperitoneally 60 min prior to LCA ligation. For mechanistic investigations, blood plasmas and left ventricle tissues were collected, and a hypothesis-driven selection of protein or mRNA targets was investigated. Surprisingly, hearts from NLRP3-deficient mice featured larger infarct size than WT mice (p = 0.0048). In general, there were only modest changes with no significant pattern in myocardial infiltration of neutrophils and macrophages and systemic and myocardial cytokine expression between the three genotypes. Preconditioning with the TLR2 agonist Pam3CSK4 induced Akt phosphorylation and reduced infarct size in WT but not NLRP3 -or ASC -deficient hearts.
  
  
  CONCLUSIONS
  Absence of NLRP3 results in increased myocardial infarct size after in vivo ischemia reperfusion, seemingly due to dysfunction of the cardioprotective RISK pathway. Our data imply that NLRP3 contributes to cardio-protection during I/R and do not support a role for NLRP3 or ASC inhibition in the management of acute MI including revascularization therapy.
authors.affiliation: Research institute for internal medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Centre for Heart Failure Research, University of Oslo, Oslo, Norway; K.G.Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway. Electronic address: oystein.sandanger@rr-research.no.
authors.forename: Ø
authors.initials: Ø
authors.lastname: Sandanger
authors.affiliation: Temple University School of Medicine, Philadelphia, United States.
authors.forename: E
authors.initials: E
authors.lastname: Gao
authors.affiliation: Research institute for internal medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Centre for Heart Failure Research, University of Oslo, Oslo, Norway; K.G.Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.
authors.forename: T
authors.initials: T
authors.lastname: Ranheim
authors.affiliation: Institute of Basic Medical Sciences, Department of Physiology, University of Oslo, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: M
authors.initials: M
authors.lastname: Bliksøen
authors.affiliation: Centre for Heart Failure Research, University of Oslo, Oslo, Norway; Institute for Surgical Research, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: O J
authors.initials: OJ
authors.lastname: Kaasbøll
authors.affiliation: Research institute for internal medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Centre for Heart Failure Research, University of Oslo, Oslo, Norway; K.G.Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.
authors.forename: K
authors.initials: K
authors.lastname: Alfsnes
authors.affiliation: Research institute for internal medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Centre for Heart Failure Research, University of Oslo, Oslo, Norway; K.G.Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.
authors.forename: Ståle H
authors.initials: SH
authors.lastname: Nymo
authors.affiliation: Research institute for internal medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G.Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.
authors.forename: A
authors.initials: A
authors.lastname: Rashidi
authors.affiliation: Research institute for internal medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Centre for Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: I K
authors.initials: IK
authors.lastname: Ohm
authors.affiliation: Centre for Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: Håvard
authors.initials: H
authors.lastname: Attramadal
authors.affiliation: Research institute for internal medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G.Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: P
authors.initials: P
authors.lastname: Aukrust
authors.affiliation: Research institute for internal medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Centre for Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: L E
authors.initials: LE
authors.lastname: Vinge
authors.affiliation: Research institute for internal medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Centre for Heart Failure Research, University of Oslo, Oslo, Norway; K.G.Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: A
authors.initials: A
authors.lastname: Yndestad
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D005260:Female; D007113:Immunity, Innate / Q000276:immunology*; D058847:Inflammasomes / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000276:immunology* / Q000473:pathology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse
keywords: ASC; Acute coronary syndrome; Heart; Inflammasome; Inflammation; Ischemia-reperfusion; NLRP3; Revascularization