title: Paigen diet-fed apolipoprotein E knockout mice develop severe pulmonary hypertension in an interleukin-1-dependent manner.
abstract: Inflammatory mechanisms are proposed to play a significant role in the pathogenesis of pulmonary arterial hypertension (PAH). Previous studies have described PAH in fat-fed apolipoprotein E knockout (ApoE(-/-)) mice. We have reported that signaling in interleukin-1-receptor-knockout (IL-1R1(-/-)) mice leads to a reduction in diet-induced systemic atherosclerosis. We subsequently hypothesized that double-null (ApoE(-/-)/IL-1R1(-/-)) mice would show a reduced PAH phenotype compared with that of ApoE(-/-) mice. Male IL-1R1(-/-), ApoE(-/-), and ApoE(-/-)/IL-1R1(-/-) mice were fed regular chow or a high-fat diet (Paigen diet) for 8 weeks before phenotyping for PAH. No abnormal phenotype was observed in the IL-1R1(-/-) mice. Fat-fed ApoE(-/-) mice developed significantly increased right ventricular systolic pressure and substantial pulmonary vascular remodeling. Surprisingly, ApoE(-/-)/IL-1R1(-/-) mice showed an even more severe PAH phenotype. Further molecular investigation revealed the expression of a putative, alternatively primed IL-1R1 transcript expressed within the lungs but not aorta of ApoE(-/-)/IL-1R1(-/-) mice. Treatment of ApoE(-/-) and ApoE(-/-)/IL-1R1(-/-) mice with IL-1-receptor antagonist prevented progression of the PAH phenotype in both strains. Blocking IL-1 signaling may have beneficial effects in treating PAH, and alternative IL-1-receptor signaling in the lung may be important in driving PAH pathogenesis.
authors.affiliation: Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom. a.lawrie@sheffield.ac.uk
authors.forename: Allan
authors.initials: A
authors.lastname: Lawrie
authors.forename: Abdul G
authors.initials: AG
authors.lastname: Hameed
authors.forename: Janet
authors.initials: J
authors.lastname: Chamberlain
authors.forename: Nadine
authors.initials: N
authors.lastname: Arnold
authors.forename: Aneurin
authors.initials: A
authors.lastname: Kennerley
authors.forename: Kay
authors.initials: K
authors.lastname: Hopkinson
authors.forename: Josephine
authors.initials: J
authors.lastname: Pickworth
authors.forename: David G
authors.initials: DG
authors.lastname: Kiely
authors.forename: David C
authors.initials: DC
authors.lastname: Crossman
authors.forename: Sheila E
authors.initials: SE
authors.lastname: Francis
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D018450:Disease Progression; D005247:Feeding Behavior / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000150:complications / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology / Q000627:therapeutic use; D007375:Interleukin-1 / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D053244:Osteoprotegerin / Q000378:metabolism; D010641:Phenotype; D011651:Pulmonary Artery / Q000473:pathology / Q000503:physiopathology; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D016278:Ventricular Function, Right / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D001057:Apolipoproteins E; D015415:Biomarkers; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D053244:Osteoprotegerin; D017472:Receptors, Interleukin-1; D053221:TNF-Related Apoptosis-Inducing Ligand