title: Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice.
abstract: Pulmonary hypertension is a serious condition that can lead to premature death. The mechanisms involved are incompletely understood although a role for the immune system has been suggested. Inflammasomes are part of the innate immune system and consist of the effector caspase-1 and a receptor, where nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) is the best characterized and interacts with the adaptor protein apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC). To investigate whether ASC and NLRP3 inflammasome components are involved in hypoxia-induced pulmonary hypertension, we utilized mice deficient in ASC and NLRP3. Active caspase-1, IL-18, and IL-1β, which are regulated by inflammasomes, were measured in lung homogenates in wild-type (WT), ASC(-/-), and NLRP3(-/-) mice, and phenotypical changes related to pulmonary hypertension and right ventricular remodeling were characterized after hypoxic exposure. Right ventricular systolic pressure (RVSP) of ASC(-/-) mice was significantly lower than in WT exposed to hypoxia (40.8 ± 1.5 mmHg vs. 55.8 ± 2.4 mmHg, P < 0.001), indicating a substantially reduced pulmonary hypertension in mice lacking ASC. Magnetic resonance imaging further supported these findings by demonstrating reduced right ventricular remodeling. RVSP of NLRP3(-/-) mice exposed to hypoxia was not significantly altered compared with WT hypoxia. Whereas hypoxia increased protein levels of caspase-1, IL-18, and IL-1β in WT and NLRP3(-/-) mice, this response was absent in ASC(-/-) mice. Moreover, ASC(-/-) mice displayed reduced muscularization and collagen deposition around arteries. In conclusion, hypoxia-induced elevated right ventricular pressure and remodeling were attenuated in mice lacking the inflammasome adaptor protein ASC, suggesting that inflammasomes play an important role in the pathogenesis of pulmonary hypertension.
authors.affiliation: Department of Pulmonary Medicine, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; Center for Heart Failure Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; cero.fadila@medisin.uio.no.
authors.forename: Fadila Telarevic
authors.initials: FT
authors.lastname: Cero
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; Center for Heart Failure Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway;
authors.forename: Vigdis
authors.initials: V
authors.lastname: Hillestad
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; Center for Heart Failure Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; K.G. Jebsen Inflammation Research Center, Faculty of Medicine, University of Oslo, Oslo, Norway;
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.affiliation: Center for Heart Failure Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet and University of Oslo, Oslo, Norway; K.G. Jebsen Inflammation Research Center, Faculty of Medicine, University of Oslo, Oslo, Norway;
authors.forename: Arne
authors.initials: A
authors.lastname: Yndestad
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet and University of Oslo, Oslo, Norway; K.G. Jebsen Inflammation Research Center, Faculty of Medicine, University of Oslo, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet and University of Oslo, Oslo, Norway;
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.affiliation: Center for Heart Failure Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet and University of Oslo, Oslo, Norway; K.G. Jebsen Inflammation Research Center, Faculty of Medicine, University of Oslo, Oslo, Norway;
authors.forename: Trine
authors.initials: T
authors.lastname: Ranheim
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; Center for Heart Failure Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; Department of Genetics, Harvard Medical School, Boston, Massachusetts;
authors.forename: Ida Gjervold
authors.initials: IG
authors.lastname: Lunde
authors.affiliation: Center for Heart Failure Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet and University of Oslo, Oslo, Norway;
authors.forename: Maria Belland
authors.initials: MB
authors.lastname: Olsen
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts; Centre of Inflammation Research, Department of Cancer Research and Molecular Medicine, NTNU, Trondheim, Norway;
authors.forename: Egil
authors.initials: E
authors.lastname: Lien
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; Center for Heart Failure Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway;
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; Center for Heart Failure Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway;
authors.forename: Solveig Bjærum
authors.initials: SB
authors.lastname: Haugstad
authors.affiliation: Department of Pathology, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway.
authors.forename: Else Marit
authors.initials: EM
authors.lastname: Løberg
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; Center for Heart Failure Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway;
authors.forename: Geir
authors.initials: G
authors.lastname: Christensen
authors.affiliation: Department of Pulmonary Medicine, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; Center for Heart Failure Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway;
authors.forename: Karl-Otto
authors.initials: KO
authors.lastname: Larsen
authors.affiliation: Department of Pulmonary Medicine, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway;
authors.forename: Ole Henning
authors.initials: OH
authors.lastname: Skjønsberg
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D001158:Arteries / Q000473:pathology; D053468:CARD Signaling Adaptor Proteins; D015687:Cell Hypoxia; D003094:Collagen / Q000378:metabolism; D015870:Gene Expression; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism; D058847:Inflammasomes / Q000378:metabolism*; D020382:Interleukin-18 / Q000097:blood; D007962:Leukocytes / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D020257:Ventricular Remodeling
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D058847:Inflammasomes; D020382:Interleukin-18; C498534:Pycard protein, mouse; D003094:Collagen
keywords: inflammation; innate immunity; pulmonary vasculature