In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 116, No. suppl_16 ( 2007-10-16)
Abstract:
The cytokine interleukin (IL)-1 is an important mediator of inflammation and cardiovascular disease. Activity of this cytokine is modulated endogenously via IL-1 receptor antagonist (IL-1Ra). We have shown that IL-1Ra-deficient (IL-1Ra −/− ) mice develop degenerative aortic valve stenosis (AS) that is the most common valvular disease in Western countries. The objective of this study is to determine the mechanisms by which deficiency of IL-1Ra may promote AS. Method and Results : IL-1Ra −/− mice (backcrossed 8 generations to the BALB/c background) and wild-type (WT) mice did not differ with regard to body weight, heart weight, and systolic arterial pressure. Furthermore, no significant differences in plasma lipid levels were observed between IL-1Ra −/− and WT mice. However histological analysis revealed that IL-1Ra −/− mice developed aortitis and showed increased aortic valve leaflet thickness compared to WT mice at the age of 12 weeks (p 〈 0.001). Echo cardiograms also revealed that IL-1Ra −/− mice displayed higher transvalvular velocities than WT mice at the age of 40 weeks (p 〈 0.01). These findings showed that IL-1Ra−/− mice spontaneously developed AS. In this study, we examined the role of T cells in development of AS by peripheral T cell transplantation. Transplantation of T cells from WT mice induced mild swelling of aortic valve leaflet in nu/nu mice. In contrast, T cells from IL-1Ra −/− mice induced an increase in aortic valve thickness in nu/nu mice. We next checked T cell function. After anti-CD3 antibody stimulation, IL-1Ra −/− T cells produced much higher levels of tumor necrosis factor (TNF)-α in culture supernatants compared to those from WT mice (p 〈 0.001). Furthermore, in IL-1Ra −/− mice, TNF-α protein levels were higher than in WT mice (106.2±12.5 vs. 216.5±12.5 pg/mL, p 〈 0.001) in vivo. Finally, we studied the roles of TNF-α in the development of AS in IL-1Ra −/− mice by generating double gene deficient (TNF-α −/− / IL-1Ra −/− ) mice. Interestingly, TNF-α −/− /IL-1Ra −/− mice did not develop AS. Conclusions : These findings suggest that IL-1Ra deficiency in T cells disrupts homeostasis of the immune system and TNF-α plays an important role in the development of AS in IL-1Ra −/− mice. These novel findings provide a clue for the development of new therapies for AS.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/circ.116.suppl_16.II_245-a
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2007
detail.hit.zdb_id:
1466401-X
