title: Pharmacological Inhibition of NLRP3 Inflammasome Attenuates Myocardial Ischemia/Reperfusion Injury by Activation of RISK and Mitochondrial Pathways.
abstract: Although the nucleotide-binding oligomerization domain- (NOD-) like receptor pyrin domain containing 3 (NLRP3) inflammasome has been recently detected in the heart, its role in cardiac ischemia/reperfusion (IR) is still controversial. Here, we investigate whether a pharmacological modulation of NLRP3 inflammasome exerted protective effects in anex vivomodel of IR injury. Isolated hearts from male Wistar rats (5-6 months old) underwent ischemia (30 min) followed by reperfusion (20 or 60 min) with and without pretreatment with the recently synthetized NLRP3 inflammasome inhibitor INF4E (50μM, 20 min before ischemia). INF4E exerted protection against myocardial IR, shown by a significant reduction in infarct size and lactate dehydrogenase release and improvement in postischemic left ventricular pressure. The formation of the NLRP3 inflammasome complex was induced by myocardial IR and attenuated by INF4E in a time-dependent way. Interestingly, the hearts of the INF4E-pretreated animals displayed a marked improvement of the protective RISK pathway and this effect was associated increase in expression of markers of mitochondrial oxidative phosphorylation. Our results demonstrate for the first time that INF4E protected against the IR-induced myocardial injury and dysfunction, by a mechanism that involves inhibition of the NLRP3 inflammasome, resulting in the activation of the prosurvival RISK pathway and improvement in mitochondrial function.
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Torino, Italy.
authors.forename: Raffaella
authors.identifier: 0000-0002-0104-6129
authors.initials: R
authors.lastname: Mastrocola
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Torino, Italy.
authors.forename: Claudia
authors.identifier: 0000-0002-9696-0449
authors.initials: C
authors.lastname: Penna
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Torino, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Tullio
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Torino, Italy.
authors.forename: Saveria
authors.initials: S
authors.lastname: Femminò
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Torino, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Nigro
authors.affiliation: Department of Drug Science and Technology, University of Turin, Torino, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Chiazza
authors.affiliation: Department of Drug Science and Technology, University of Turin, Torino, Italy.
authors.forename: Loredana
authors.identifier: 0000-0002-1080-0322
authors.initials: L
authors.lastname: Serpe
authors.affiliation: Department of Drug Science and Technology, University of Turin, Torino, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Collotta
authors.affiliation: Department of Life Sciences and Systems Biology, University of Turin, Torino, Italy.
authors.forename: Giuseppe
authors.identifier: 0000-0003-4147-159X
authors.initials: G
authors.lastname: Alloatti
authors.affiliation: Department of Drug Science and Technology, University of Turin, Torino, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Cocco
authors.affiliation: Department of Drug Science and Technology, University of Turin, Torino, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Bertinaria
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Torino, Italy.
authors.forename: Pasquale
authors.identifier: 0000-0002-4386-1383
authors.initials: P
authors.lastname: Pagliaro
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Torino, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Aragno
authors.affiliation: Department of Drug Science and Technology, University of Turin, Torino, Italy.
authors.forename: Massimo
authors.identifier: 0000-0001-8782-3496
authors.initials: M
authors.lastname: Collino
mesh_terms: D000818:Animals; D004734:Energy Metabolism / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D066298:In Vitro Techniques; D058847:Inflammasomes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001678:Organelle Biogenesis; D011494:Protein Kinases / Q000378:metabolism*; D017208:Rats, Wistar; D015398:Signal Transduction
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D007770:L-Lactate Dehydrogenase; D011494:Protein Kinases