title: The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury.
abstract: OBJECTIVE
  Nucleotide-binding oligomerization domain-Like Receptor with a Pyrin domain 3 (NLRP3) is considered necessary for initiating a profound sterile inflammatory response. NLRP3 forms multi-protein complexes with Apoptosis-associated Speck-like protein containing a Caspase recruitment domain (ASC) and Caspase-1, which activate pro-interleukin-1β (IL-1β) and pro-IL-18. The role of NLRP3 in cardiac cells is not known. Thus, we investigated the expression and function of NLRP3 during myocardial ischaemia.
  
  
  RESULTS
  Myocardial infarction (MI) was induced in adult C57BL/6 mice and Wistar rats by ligation of the coronary artery. A marked increase in NLRP3, IL-1β, and IL-18 mRNA expression was found in the left ventricle after MI, primarily located to myocardial fibroblasts. In vitro studies in cells from adult mice showed that myocardial fibroblasts released IL-1β and IL-18 when primed with lipopolysaccharide and subsequently exposed to the danger signal adenosine triphosphate, a molecule released after tissue damage during MI. When hearts were isolated from NLRP3-deficient mice, perfused and subjected to global ischaemia and reperfusion, a marked improvement of cardiac function and reduction of hypoxic damage was found compared with wild-type hearts. This was not observed in ASC-deficient hearts, potentially reflecting a protective role of other ASC-dependent inflammasomes or inflammasome-independent effects of NLRP3.
  
  
  CONCLUSIONS
  This study shows that the NLRP3 inflammasome is up-regulated in myocardial fibroblasts post-MI, and may be a significant contributor to infarct size development during ischaemia-reperfusion.
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo N-0027, Norway.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Sandanger
authors.forename: Trine
authors.initials: T
authors.lastname: Ranheim
authors.forename: Leif Erik
authors.initials: LE
authors.lastname: Vinge
authors.forename: Marte
authors.initials: M
authors.lastname: Bliksøen
authors.forename: Katrine
authors.initials: K
authors.lastname: Alfsnes
authors.forename: Alexandra V
authors.initials: AV
authors.lastname: Finsen
authors.forename: Christen P
authors.initials: CP
authors.lastname: Dahl
authors.forename: Erik T
authors.initials: ET
authors.lastname: Askevold
authors.forename: Geir
authors.initials: G
authors.lastname: Florholmen
authors.forename: Geir
authors.initials: G
authors.lastname: Christensen
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Egil
authors.initials: E
authors.lastname: Lien
authors.forename: Guro
authors.initials: G
authors.lastname: Valen
authors.forename: Terje
authors.initials: T
authors.lastname: Espevik
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.forename: Arne
authors.initials: A
authors.lastname: Yndestad
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D006352:Heart Ventricles / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011188:Potassium / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D051193:Toll-Like Receptors / Q000378:metabolism; D015854:Up-Regulation; D016277:Ventricular Function, Left
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C573346:Nlrp3 protein, rat; C498534:Pycard protein, mouse; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D051193:Toll-Like Receptors; D000255:Adenosine Triphosphate; D020170:Caspase 1; D011188:Potassium
keywords: Heart; IL-1β; Inflammasome; Ischaemia–reperfusion; Myocardial infarction