title: Inhibition of the NLRP3 inflammasome limits the inflammatory injury following myocardial ischemia-reperfusion in the mouse.
abstract: BACKGROUND
  Successful reperfusion is the most effective strategy to reduce ischemic injury in acute myocardial infarction (AMI). Ischemic injury, however, also triggers a secondary ischemia-independent injury, known as reperfusion injury, contributing to the overall infarct size. We hypothesize that inhibition of the Nod-like Receptor Protein-3 (NLRP3) inflammasome limits infarct size following myocardial ischemia/reperfusion (I/R), by inhibiting the inflammatory component of the reperfusion injury.
  
  
  METHODS
  CD-1 male mice underwent transient ligation of the left anterior descending coronary artery for 30 or 75min followed by reperfusion. Infarct size was measured at 1, 3 and 24h. A NLRP3 inflammasome inhibitor (NLRP3inh) or vehicle was administrated immediately at time of reperfusion or with a delay of 1 or 3h of reperfusion.
  
  
  RESULTS
  A time-dependent increase in infarct size was measured at 1, 3, and 24h after reperfusion (11±2%, 30±5% and 43±4% of the area at risk respectively; P<0.001 for trend). NLRP3 myocardial expression was significantly increased at 24h and 6h vs 3h (P<0.01). Administration of the NLRP3inh at reperfusion did not reduce infarct size at 3h, while it significantly reduced infarct size at 24h (-56% vs vehicle, P<0.01). The NLRP3inh given 1h after reperfusion also significantly decreased caspase-1 activity and infarct size measured at 24h, whereas the NLRP3inh did not when given with a delay of 3h.
  
  
  CONCLUSIONS
  Pharmacological inhibition of the NLRP3 inflammasome within 1h of reperfusion limits the secondary inflammatory injury and infarct size following myocardial ischemia-reperfusion in the mouse.
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, United States; Department of Surgery, Division of Cardio-thoracic Surgery, Virginia Commonwealth University, United States; Johnson Research Center for Critical Care, Virginia Commonwealth University, United States.
authors.forename: Stefano
authors.initials: S
authors.lastname: Toldo
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, United States; Johnson Research Center for Critical Care, Virginia Commonwealth University, United States.
authors.forename: Carlo
authors.initials: C
authors.lastname: Marchetti
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, United States; Johnson Research Center for Critical Care, Virginia Commonwealth University, United States.
authors.forename: Adolfo G
authors.initials: AG
authors.lastname: Mauro
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, United States.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chojnacki
authors.affiliation: Department of Pharmacotherapy and Outcome Sciences, Virginia Commonwealth University, United States.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Mezzaroma
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, United States.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Carbone
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, United States.
authors.forename: Shijun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, United States.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Van Tassell
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, United States.
authors.forename: Fadi N
authors.initials: FN
authors.lastname: Salloum
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, United States; Johnson Research Center for Critical Care, Virginia Commonwealth University, United States. Electronic address: antonio.abbate@vcuhealth.org.
authors.forename: Antonio
authors.initials: A
authors.lastname: Abbate
mesh_terms: D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology / Q000627:therapeutic use; D058847:Inflammasomes / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism*; D015425:Myocardial Reperfusion / Q000009:adverse effects; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: D002317:Cardiovascular Agents; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse
keywords: Infarction; Inflammasome; Inflammation; Injury; Ischemia; Reperfusion