Beta glycosphingolipids suppress rank expression and inhibit natural killer T cell and CD8+ accumulation in alleviating aortic valve calcification.
CD8 lymphocytes play a role in aortic valve inflammation leading to aortic valve calcification (AVC). RANK is a transmembrane protein that is important in osteoclast differentiation and calcification. Beta-glucosylceramide (beta-GC) together with beta-lactosylceramide (beta-LC), the 1:1 combination of beta- glucosylceramide and beta-lactosylceramide, designated IGL, exerts an immune modulatory effect in various inflammatory disorders in a CD8- and NKT (natural killer T cell)-dependent manner. We hypothesized that IGL may affect the inflammatory condition associated with AVC. AVC was induced in rats by oral administration of a high-adenine, high-phosphorus diet and was assessed by multislice computer tomography. Administration of this diet was associated with a marked increase in CD8 and NKT lymphocyte accumulation in the aortic valve. Administration of IGL led to marked suppression of RANK expression, associated with inhibition of both NKT and CD8 lymphocyte accumulation in the aortic valve. These effects were associated with a significant improvement in the degree of AVC in IGL-treated animals (25 and 53 by Agatston Score, in IGL-treated and controls, respectively). CD8 and NKT lymphocytes play a role in the pathogenesis of AVC, and RANK-mediated NKT inhibition by beta-glycosphingolipids can alleviate AVC.
Shuvy
M
M
Liver Unit, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
Ben Ya'acov
A
A
Zolotarov
L
L
Lotan
C
C
Ilan
Y
Y
D000818:Animals; D001021:Aortic Valve / Q000000981:diagnostic imaging / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002114:Calcinosis / Q000000981:diagnostic imaging / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D004195:Disease Models, Animal; D015536:Down-Regulation; D006028:Glycosphingolipids / Q000378:metabolism*; D006349:Heart Valve Diseases / Q000000981:diagnostic imaging / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D054559:Hyperphosphatemia / Q000276:immunology; D008297:Male; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism*; D051437:Renal Insufficiency / Q000276:immunology; D012720:Severity of Illness Index; D013997:Time Factors; D014057:Tomography, X-Ray Computed
D006028:Glycosphingolipids; D053246:Receptor Activator of Nuclear Factor-kappa B