title: The Nlrp3 inflammasome promotes myocardial dysfunction in structural cardiomyopathy through interleukin-1β.
abstract: Heart failure is associated with a low-grade and chronic cardiac inflammation that impairs function; however, the mechanisms by which this sterile inflammation occurs in structural heart disease remain poorly defined. Cardiac-specific heterozygous overexpression of the calcineurin transgene (CNTg) in mice results in cardiac hypertrophy, inflammation, apoptosis and ventricular dilatation. We hypothesized that activation of the Nlrp3 inflammasome, an intracellular danger-sensing pathway required for processing the pro-inflammatory cytokine interleukin-1β (IL-1β), may contribute to myocardial dysfunction and disease progression. Here we report that Nlrp3 mRNA was increased in CNTg mice compared with wild-type. Consistent with inflammasome activation, CNTg animals had increased conversion of pro-caspase-1 to cleaved and activated forms, as well as markedly increased serum IL-1β. Blockade of IL-1β signalling via chronic IL-1 receptor antagonist therapy reduced cardiac inflammation and myocyte pathology in CNTg mice, resulting in improved systolic performance. Furthermore, genetic ablation of Nlrp3 in CNTg mice reduced pro-inflammatory cytokine maturation and cardiac inflammation, as well as improving systolic performance. These findings indicate that activation of the Nlrp3 inflammasome in CNTg mice promotes myocardial inflammation and systolic dysfunction through the production of pro-inflammatory IL-1β. Blockade of IL-1β signalling with the IL-1 receptor antagonist reverses these phenotypes and offers a possible therapeutic approach in the management of heart failure.
authors: Department of Medicine, Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada.
authors: Nathan A
authors: NA
authors: Bracey
authors: Paul L
authors: PL
authors: Beck
authors: Daniel A
authors: DA
authors: Muruve
authors: Simon A
authors: SA
authors: Hirota
authors: Jiqing
authors: J
authors: Guo
authors: Habib
authors: H
authors: Jabagi
authors: James R
authors: JR
authors: Wright
authors: Justin A
authors: JA
authors: Macdonald
authors: James P
authors: JP
authors: Lees-Miller
authors: Daniel
authors: D
authors: Roach
authors: Lisa M
authors: LM
authors: Semeniuk
authors: Henry J
authors: HJ
authors: Duff
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D009202:Cardiomyopathies / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004792:Enzyme Precursors; D006333:Heart Failure / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D058847:Inflammasomes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000097:blood / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009205:Myocarditis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D009206:Myocardium / Q000276:immunology* / Q000473:pathology; D041681:NIH 3T3 Cells; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020127:Recovery of Function; D015398:Signal Transduction; D013599:Systole; D013997:Time Factors; D016277:Ventricular Function, Left
chemical_list: D002352:Carrier Proteins; D004792:Enzyme Precursors; D058847:Inflammasomes; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017472:Receptors, Interleukin-1; D019703:Calcineurin; D020170:Caspase 1