title: Maladaptive Modulations of NLRP3 Inflammasome and Cardioprotective Pathways Are Involved in Diet-Induced Exacerbation of Myocardial Ischemia/Reperfusion Injury in Mice.
abstract: Excessive fatty acids and sugars intake is known to affect the development of cardiovascular diseases, including myocardial infarction. However, the underlying mechanisms are ill defined. Here we investigated the balance between prosurvival and detrimental pathways within the heart of C57Bl/6 male mice fed a standard diet (SD) or a high-fat high-fructose diet (HFHF) for 12 weeks and exposed to cardiac ex vivo ischemia/reperfusion (IR) injury. Dietary manipulation evokes a maladaptive response in heart mice, as demonstrated by the shift of myosin heavy chain isoform content from α to β, the increased expression of the Nlrp3 inflammasome and markers of oxidative metabolism, and the downregulation of the hypoxia inducible factor- (HIF-)2α and members of the Reperfusion Injury Salvage Kinases (RISK) pathway. When exposed to IR, HFHF mice hearts showed greater infarct size and lactic dehydrogenase release in comparison with SD mice. These effects were associated with an exacerbated overexpression of Nlrp3 inflammasome, resulting in marked caspase-1 activation and a compromised activation of the cardioprotective RISK/HIF-2α pathways. The common mechanisms of damage here reported lead to a better understanding of the cross-talk among prosurvival and detrimental pathways leading to the development of cardiovascular disorders associated with metabolic diseases.
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, Orbassano, 10043 Torino, Italy.
authors.forename: Raffaella
authors.identifier: 0000-0002-0104-6129
authors.initials: R
authors.lastname: Mastrocola
authors.affiliation: Department of Drug Science and Technology, University of Turin, Corso Raffaello 33, 10125 Torino, Italy.
authors.forename: Massimo
authors.identifier: 0000-0001-8782-3496
authors.initials: M
authors.lastname: Collino
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, Orbassano, 10043 Torino, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Penna
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, Orbassano, 10043 Torino, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Nigro
authors.affiliation: Department of Drug Science and Technology, University of Turin, Corso Raffaello 33, 10125 Torino, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Chiazza
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, Orbassano, 10043 Torino, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Fracasso
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, Orbassano, 10043 Torino, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Tullio
authors.affiliation: Department of Life Sciences and Systems Biology, University of Torino, via Accademia Albertina 13, 10123 Torino, Italy; National Institute for Cardiovascular Research, via Irnerio 48, 40126 Bologna, Italy.
authors.forename: Giuseppe
authors.identifier: 0000-0003-4147-159X
authors.initials: G
authors.lastname: Alloatti
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, Orbassano, 10043 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, Regione Gonzole 10, Orbassano, 10043 Torino, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Aragno
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002470:Cell Survival; D004032:Diet / Q000009:adverse effects*; D059305:Diet, High-Fat / Q000009:adverse effects; D018450:Disease Progression; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D058847:Inflammasomes / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009203:Myocardial Infarction / Q000150:complications / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D018384:Oxidative Stress; D021381:Protein Transport; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D002352:Carrier Proteins; D051275:Glucose Transporter Type 4; C485502:HIF-2 protein, mouse; D058847:Inflammasomes; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D014157:Transcription Factors; D007770:L-Lactate Dehydrogenase