Influence of receptor activator of nuclear factor kappa B on human aortic valve myofibroblasts.
Calcific aortic valve stenosis, the main heart valve disease in the elderly, is based on progressive calcification and fibrous thickening of the valve. Several reports addressed the pathogenesis of tissue calcification in this disorder, but few data exist on the molecular mechanisms of the fibrosis and remodeling of the extracellular matrix. The cytokine "receptor activator of nuclear factor kappa B ligand" (RANKL), is expressed in stenotic aortic valves and involved in valvular calcification during calcific aortic valve stenosis. The present study aimed to assess the influence of RANKL on the molecular mechanisms of connective tissue remodeling. In an established cell culture model of primary human aortic valve myofibroblasts, stimulation with RANKL increased cell proliferation as compared to medium alone. Matrix metalloproteinase (MMP)-1 was detectable time-dependently in conditioned media from RANKL-stimulated cells, but absent in media from control cells. MMP-1 activity was increased by RANKL, as measured by collagenase activity assay. Zymography showed an increase in active MMP-2 in RANKL-stimulated cells. These results support the concept that MMPs are involved in the connective tissue remodeling during calcific aortic valve stenosis. RANKL might regulate this process by promoting cell proliferation and MMP expression and activation.
Kaden
Jens J
JJ
Department of Medicine (Cardiology, Angiology, Pneumology), Faculty of Clinical Medicine Mannheim, University of Heidelberg, Mannheim, Germany. jens.kaden@med.ma.uni-heidelberg.de
Dempfle
Carl-Erik
CE
Kiliç
Refika
R
Sarikoç
Aslihan
A
Hagl
Siegfried
S
Lang
Siegfried
S
Brueckmann
Martina
M
Borggrefe
Martin
M
D001021:Aortic Valve / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D001024:Aortic Valve Stenosis / Q000201:enzymology / Q000473:pathology; D002114:Calcinosis / Q000473:pathology; D002352:Carrier Proteins / Q000494:pharmacology*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000032:analysis / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000032:analysis / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B
D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1