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

Lawrie, Allan, Hameed, Abdul G, Chamberlain, Janet, Arnold, Nadine, Kennerley, Aneurin, Hopkinson, Kay, Pickworth, Josephine, Kiely, David G, Crossman, David C and Francis, Sheila 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. 1693-705. ISSN 0002-9440

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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.

Item Type:	Article
Additional Information:	Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Uncontrolled 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
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Groups > Norwich Clinical Trials Unit
Depositing User:	Pure Connector
Date Deposited:	20 Jan 2014 16:04
Last Modified:	24 Oct 2022 05:34
URI:	https://ueaeprints.uea.ac.uk/id/eprint/46186
DOI:	10.1016/j.ajpath.2011.06.037

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