Regular article
Cardiovascular, pulmonary, and renal pathology
Paigen Diet–Fed Apolipoprotein E Knockout Mice Develop Severe Pulmonary Hypertension in an Interleukin-1–Dependent Manner

https://doi.org/10.1016/j.ajpath.2011.06.037Get rights and content
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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.

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Supported by a Medical Research Council Career Development Award (G0800318 to A.L.); a British Heart Foundation Clinical Research Training Fellowship (FS/08/061/25740 to A.G.H.); the National Institute for Health Research Sheffield Cardiovascular Biomedical Research Unit (N.A.); and the National Institute for Health Research via its Biomedical Research Units funding scheme (N.A. and D.C.).

Human IL-1Ra and placebo were obtained under MTA 200517250-001 from Amgen, Inc. (Thousand Oaks, CA).

Current address of D.C.C., Norwich Medical School, University of East Anglia, Norwich, UK.