Paigen diet-fed apolipoprotein E knockout mice develop severe pulmonary hypertension in an interleukin-1-dependent manner

Allan Lawrie, Abdul G Hameed, Janet Chamberlain, Nadine Arnold, Aneurin Kennerley, Kay Hopkinson, Josephine Pickworth, David G Kiely, David C Crossman, Sheila E Francis

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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.
Original languageEnglish
Pages (from-to)1693-705
Number of pages13
JournalAmerican Journal of Pathology
Volume179
Issue number4
DOIs
Publication statusPublished - Oct 2011

Keywords

  • Animals
  • Apolipoproteins E
  • Biological Markers
  • Diet, High-Fat
  • Disease Progression
  • Feeding Behavior
  • Hemodynamics
  • Hypertension, Pulmonary
  • Hypertrophy, Right Ventricular
  • Inflammation Mediators
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1
  • Lung
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Organ Size
  • Osteoprotegerin
  • Phenotype
  • Pulmonary Artery
  • Receptors, Interleukin-1
  • TNF-Related Apoptosis-Inducing Ligand
  • Up-Regulation
  • Ventricular Function, Right
  • Ventricular Remodeling

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