Division of Cardiothoracic Surgery, the University of Colorado, Aurora, CO 80045, USA.
J Thorac Cardiovasc Surg. 2011 Feb;141(2):481-6. doi: 10.1016/j.jtcvs.2010.11.002.
Aortic stenosis is an inflammatory disease, associated with increased tissue levels of interleukin-1 beta. We hypothesized that the antagonist of interleukin-1 beta, interleukin-1 receptor antagonist, is deficient in aortic valves and that its production by aortic valve interstitial cells is less in cells from stenotic valves than from controls.
Valve leaflets from stenotic aortic valves (n=6) and from valves from hearts explanted at the time of cardiac transplantation (n=6) were studied by immunostaining for interleukin-1 receptor antagonist. Aortic valve interstitial cells were isolated from valves, and receptor antagonist levels were determined from cell lysates (enzyme-linked immunosorbent assay). Osteogenic phenotype changes in valve cells stimulated by toll-like receptors 2 and 4 were determined by immunoblotting for bone morphogenetic protein-2 after treatment with and without interleukin-1 receptor antagonist (100 μg/mL). Statistics were by analysis of variance.
Interleukin-1 receptor antagonist was abundant in nonstenotic aortic valve leaflets and virtually absent in leaflets from stenotic valves. Aortic valve interstitial cells from grossly normal leaflets produced significantly more receptor antagonist at baseline and in response to toll-like receptor 2 and 4 stimulation, than did cells from diseased valves (P<0.05). Interleukin-1 receptor antagonist was able to significantly attenuate toll-like receptor 2, but not toll-like receptor 4, stimulated bone morphogenetic protein-2 production in aortic valve interstitial cells (P<.05).
Interleukin-1 receptor antagonist-mediated mechanisms of anti-inflammation are dysfunctional in stenotic valves. We conclude that such impaired mechanisms of anti-inflammation may contribute to the pathogenesis of aortic stenosis.
主动脉瓣狭窄是一种炎症性疾病，与白细胞介素-1β的组织水平升高有关。我们假设白细胞介素-1β的拮抗剂白细胞介素-1受体拮抗剂在主动脉瓣中缺乏，并且其在狭窄瓣膜中的产生量低于对照瓣膜中的产生量。
通过免疫染色研究来自狭窄主动脉瓣（n=6）和心脏移植时取出的瓣膜（n=6）的瓣叶中的白细胞介素-1受体拮抗剂。从瓣膜中分离出主动脉瓣间质细胞，并从细胞裂解物中（酶联免疫吸附试验）测定受体拮抗剂水平。通过用和不用白细胞介素-1受体拮抗剂（100μg/mL）处理后骨形态发生蛋白-2的免疫印迹测定受 Toll 样受体 2 和 4 刺激的瓣膜细胞的成骨表型变化。通过方差分析进行统计学分析。
白细胞介素-1受体拮抗剂在非狭窄主动脉瓣瓣叶中丰富，而在狭窄瓣叶中几乎不存在。大体正常瓣叶的主动脉瓣间质细胞在基线水平和对 Toll 样受体 2 和 4 刺激的反应中产生的受体拮抗剂明显多于病变瓣膜的细胞（P<0.05）。白细胞介素-1受体拮抗剂能够显著减弱 Toll 样受体 2 但不能减弱 Toll 样受体 4 刺激的骨形态发生蛋白-2产生在主动脉瓣间质细胞中（P<.05）。
在狭窄的瓣膜中，白细胞介素-1 受体拮抗剂介导的抗炎机制功能失调。我们得出结论，这种受损的抗炎机制可能导致主动脉瓣狭窄的发病机制。
