Paigen diet-fed apolipoprotein E knockout mice develop severe pulmonary hypertension in an interleukin-1-dependent manner.
Am J Pathol
; 179(4): 1693-705, 2011 Oct.
Article
en En
| MEDLINE
| ID: mdl-21835155
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Apolipoproteínas E
/
Interleucina-1
/
Dieta Alta en Grasa
/
Hipertensión Pulmonar
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Am J Pathol
Año:
2011
Tipo del documento:
Article
País de afiliación:
Reino Unido