Abstract 1522: Deficiency of Interleukin-1 Receptor Antagonist Induces Aortic Valve Disease in BALB/c Mice
Background: Degenerative aortic valve stenosis (AS) is the most common valvular disease in Western countries. Observations suggest a link between AS and inflammation. Interleukin-1 receptor antagonist (IL-1Ra) is one of the most important anti-inflammatory cytokines and crucial for homeostasis of the immune system. IL-1Ra-deficient (IL-1Ra−/ −) mice on the BALB/c background spontaneously develop aortitis, but the role of IL-1Ra in degenerative valves is poorly understood.
Methods: Using IL-1Ra−/ − mice (backcrossed 8 generations to the BALB/c background) and wild-type (WT) mice, we studied aortic valve function and histology, and examined the immunologic mechanisms involved in the development of AS by cell transplantation experiments.
Results: Transvalvular velocity and pressure gradient of IL-1Ra−/ − mice increased by 93% (P<0.01) and 289% (P<0.01), respectively, compared with WT mice. Transthoracic echocardiography also revealed that the thickness of both the interventricular septum wall and the posterior of IL-1Ra increased significantly (P<0.01). However IL-1Ra−/ −mice showed normal blood pressure. These results suggest that the pressure gradient is affected by mild AS, and left ventriclar hypertrophy may be induced by pressure overload. Infiltration of monocytes was observed in the aorta and valve, and a loss of elastic lamellae in the aortic media was observed on histological examination. Leaflet thickness was also significantly increased in IL-1Ra−/ − mice compared with WT mice. Interestingly, several areas of chondroid metaplasia were identified with the aortas of IL-1Ra−/ − mice. Bone marrow cell transplants from IL-1Ra−/ − mice induced AS in irradiated WT recipient mice. Furthermore, Transplantation of T cells from IL-1Ra−/ − mice induced AS in recipient nu/nu mice.
Conclusion: The present study shows that IL-1Ra gene deficiency in BALB/c mice led to the development of AS and inflammation. These results demonstrate that IL-1Ra is crucial for the prevention of AS during inflammation. Furthermore, we suggest that IL-1Ra deficiency in T cells are excessively activated even by physiological levels of IL-1 and may lose tolerance for aortic endothelial cell components, resulting in the development of autoimmunity and inflammation.