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25 Paigen diet-fed Apolipoprotein E knock-out mice develop severe pulmonary hypertension in an interleukin-1 dependent manner
  1. A Lawrie,
  2. A G Hameed,
  3. J Chamberlain,
  4. N Arnold,
  5. D C Crossman,
  6. S E Francis
  1. Department of Cardiovascular Science, Faculty of Medicine, Dentistry & Health, University of Sheffield Medical School, Sheffield, UK

Abstract

Pulmonary arterial hypertension (PAH) is a life threatening condition with high morbidity and mortality. Inflammatory mechanisms are proposed to play a significant role in disease progression. Previous studies have described mild PAH in western-diet fed Apolipoprotein E knock out mice (ApoE−/−). Our group has previously reported that ApoE−/− mice fed the Paigen diet develop 40% more atherosclerosis than littermates fed the western diet, and that treatment with IL-1 receptor antagonist (IL-1Ra) reduced atherosclerosis. We subsequently hypothesised that ApoE−/− fed the Paigen diet would develop a more severe pulmonary hypertension phenotype than previously reported with the western diet, and that treatment with IL-1Ra would be able to reduce this phenotype. ApoE−/− mice fed the Paigen diet for 8 weeks developed significantly increased right ventricular systolic pressure compared to chow-fed littermates mean (50 vs 23 mm Hg, n=7 p<0.01). Immunohistological analysis of the lungs revealed evidence of a severe pulmonary vasculopathy, including heavily muscularised, and obliterative lesions in the small resistance pulmonary arteries (<50 μm) in Paigen diet-fed ApoE−/− mice. The media/CSA ratio of the small (<50 μm) and medium-sized pulmonary arteries (51–100 μm) was significantly increased in the Paigen diet-fed ApoE−/− mice compared to chow-fed controls. To test whether IL-1Ra could reduce this phenotype Paigen-fed ApoE−/− mice were treated with IL-1Ra or placebo for 4 weeks via a subcutaneous osmotic mini pump, following an initial 4 weeks on diet. ApoE−/− mice treated with IL-1Ra had significantly reduced RVSP (23 mm Hg) and pulmonary vascular remodelling (55%) compared to placebo treated controls. These data suggest that IL-1Ra may have beneficial effects in treating PAH.

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