title: The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse.
abstract: Acute myocardial infarction (AMI) initiates an intense inflammatory response that promotes cardiac dysfunction, cell death, and ventricular remodeling. The molecular events underlying this inflammatory response, however, are incompletely understood. In experimental models of sterile inflammation, ATP released from dying cells triggers, through activation of the purinergic P2X7 receptor, the formation of the inflammasome, a multiprotein complex necessary for caspase-1 activation and amplification of the inflammatory response. Here we describe the presence of the inflammasome in the heart in an experimental mouse model of AMI as evidenced by increased caspase-1 activity and cytoplasmic aggregates of the three components of the inflammasome--apoptosis speck-like protein containing a caspase-recruitment domain (ASC), cryopyrin, and caspase-1, localized to the granulation tissue and cardiomyocytes bordering the infarct. Cultured adult murine cardiomyocytes also showed the inducible formation of the inflammasome associated with increased cell death. P2X7 and cryopyrin inhibition (using silencing RNA or a pharmacologic inhibitor) prevented the formation of the inflammasome and limited infarct size and cardiac enlargement after AMI. The formation of the inflammasome in the mouse heart during AMI causes additional loss of functional myocardium, leading to heart failure. Modulation of the inflammasome may therefore represent a unique therapeutic strategy to limit cell death and prevent heart failure after AMI.
authors: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Eleonora
authors: E
authors: Mezzaroma
authors: Stefano
authors: S
authors: Toldo
authors: Daniela
authors: D
authors: Farkas
authors: Ignacio M
authors: IM
authors: Seropian
authors: Benjamin W
authors: BW
authors: Van Tassell
authors: Fadi N
authors: FN
authors: Salloum
authors: Harsha R
authors: HR
authors: Kannan
authors: Angela C
authors: AC
authors: Menna
authors: Norbert F
authors: NF
authors: Voelkel
authors: Antonio
authors: A
authors: Abbate
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004452:Echocardiography; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D034622:RNA Interference; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020257:Ventricular Remodeling
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D058486:Receptors, Purinergic P2X7; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D011732:Pyridoxal Phosphate; D020170:Caspase 1