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

Lawrie, A., Hameed, A.G., Chamberlain, J., Arnold, N., Kennerley, A., Hopkinson, K., Pickworth, J., Kiely, D.G., Crossman, D.C. and Francis, S.E. (2011) Paigen diet-fed apolipoprotein E knockout mice develop severe pulmonary hypertension in an interleukin-1-dependent manner. American Journal of Pathology, 179 (4). pp. 1693-1705. ISSN 0002-9440

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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 ApaE(-/-) 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. (Am J Pathol 2011, 179:1603-1705; 10.1016/j.ajpath.2011.06.037)

Item Type: Article
Keywords: Arterial-Hypertension; Muscle-Cells; Right Heart; Receptor; Smooth; Gene; Overexpression; Inflammation; Antagonist; Cytokines
Institution: The University of Sheffield
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine (Sheffield) > Department of Cardiovascular Science
The University of Sheffield > Faculty of Science (Sheffield) > Department of Psychology (Sheffield)
Depositing User: Miss Anthea Tucker
Date Deposited: 30 Jan 2012 10:03
Last Modified: 30 Jan 2012 10:03
Published Version: http://dx.doi.org/10.1016/j.ajpath.2011.06.037
Status: Published
Publisher: Elsevier Science
Refereed: Yes
Identification Number: 10.1016/j.ajpath.2011.06.037
URI: http://eprints.whiterose.ac.uk/id/eprint/43688

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