Stenotic aortic valves have dysfunctional mechanisms of anti-inflammation: implications for aortic stenosis.
OBJECTIVE
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Division of Cardiothoracic Surgery, the University of Colorado, Aurora, CO 80045, USA.
Joon H
JH
Lee
Xianzhong
X
Meng
Michael J
MJ
Weyant
T Brett
TB
Reece
Joseph C
JC
Cleveland
David A
DA
Fullerton
D001021:Aortic Valve / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001024:Aortic Valve Stenosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D053590:Interleukin 1 Receptor Antagonist Protein / Q000172:deficiency / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D010012:Osteogenesis; D010457:Peptidoglycan / Q000494:pharmacology; D010641:Phenotype; D011994:Recombinant Proteins / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D008070:Lipopolysaccharides; D010457:Peptidoglycan; D011994:Recombinant Proteins; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4