Influence of receptor activator of nuclear factor kappa B on human aortic valve myofibroblasts

• Published in: Experimental and molecular pathology 2005-02, Vol.78 (1), p.36-40
• Main Authors: Kaden, Jens J., Dempfle, Carl-Erik, Kılıç, Refika, Sarıkoç, Aslıhan, Hagl, Siegfried, Lang, Siegfried, Brueckmann, Martina, Borggrefe, Martin
• Format: Article
• Language: English
• Subjects: Aortic Valve - drug effects; Aortic Valve - enzymology; Aortic Valve - pathology; Aortic Valve Stenosis - enzymology; Aortic Valve Stenosis - pathology; Biological and medical sciences; Calcific aortic valve stenosis; Calcinosis - pathology; Carrier Proteins - pharmacology; Cell proliferation; Cells, Cultured; Culture Media, Conditioned - chemistry; Cytokines; Extracellular matrix; Extracellular Matrix - metabolism; Fibroblasts - drug effects; Fibroblasts - enzymology; Fibroblasts - pathology; Humans; Investigative techniques, diagnostic techniques (general aspects); Matrix Metalloproteinase 1 - analysis; Matrix Metalloproteinase 1 - metabolism; Matrix Metalloproteinase 2 - analysis; Matrix Metalloproteinase 2 - metabolism; Matrix metalloproteinases; Medical sciences; Membrane Glycoproteins - pharmacology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - enzymology; Myocytes, Smooth Muscle - pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B
• ISSN: 0014-4800; 1096-0945
• DOI: 10.1016/j.yexmp.2004.09.001

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.