TY - JOUR T1 - 25 Paigen diet-fed Apolipoprotein E knock-out mice develop severe pulmonary hypertension in an interleukin-1 dependent manner JF - Heart JO - Heart SP - e7 LP - e7 DO - 10.1136/heartjnl-2011-300920b.25 VL - 97 IS - 20 AU - A Lawrie AU - A G Hameed AU - J Chamberlain AU - N Arnold AU - D C Crossman AU - S E Francis Y1 - 2011/10/15 UR - http://heart.bmj.com/content/97/20/e7.25.abstract N2 - 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. ER -