title: Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis.
abstract: Calcific aortic valve stenosis (AS), the main heart valve disease in the elderly, is characterized by extensive remodeling of the extracellular matrix. Matrix metalloproteinases (MMPs) are upregulated in calcific AS and might modulate matrix remodeling. The regulatory mechanisms are unclear. As recent studies have suggested that calcific AS might result from an inflammatory process involving leukocyte invasion and activation, the present study aimed to elucidate the role of the pro-inflammatory cytokine interleukin (IL)-1 beta on MMP expression and cell proliferation in human aortic valves. Immunohistochemistry for leukocytes, IL-1 beta and MMP-1 was performed on aortic valves with (n=6) and without (n=6) calcification obtained at valve replacement or autopsy. Stenotic valves showed marked leukocyte infiltration and associated expression of IL-1 beta and MMP-1. In control valves only scattered leukocytes, low staining for MMP-1 and no staining for IL-1 beta were present. Double-label immunostaining localized IL-1 beta expression mainly to leukocytes and MMP-1 expression to myofibroblasts. Stimulation of cultured human aortic valve myofibroblasts with IL-1 beta lead to a time-dependently increased expression of MMP-1 and MMP-2 by Western blotting and zymography, whereas MMP-9 remained unchanged. Cell proliferation was increased by IL-1 beta as determined by bromodesoxyuridine incorporation. Thus, IL-1 beta may regulate remodeling of the extracellular matrix in calcific AS.
authors: 1st Department of Medicine (Cardiology, Angiology, and Pneumology), University Hospital of Mannheim, Mannheim, Germany. jens.kaden@med.ma.uni-heidelberg.de
authors: Jens J
authors: JJ
authors: Kaden
authors: Carl-Erik
authors: CE
authors: Dempfle
authors: Rainer
authors: R
authors: Grobholz
authors: Hanh-Thai
authors: HT
authors: Tran
authors: Refika
authors: R
authors: Kiliç
authors: Aslihan
authors: A
authors: Sarikoç
authors: Martina
authors: M
authors: Brueckmann
authors: Christian
authors: C
authors: Vahl
authors: Siegfried
authors: S
authors: Hagl
authors: Karl K
authors: KK
authors: Haase
authors: Martin
authors: M
authors: Borggrefe
mesh_terms: D001024:Aortic Valve Stenosis / Q000201:enzymology / Q000473:pathology*; D001973:Bromodeoxyuridine; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000502:physiology*; D017493:Leukocyte Common Antigens / Q000032:analysis; D007962:Leukocytes / Q000473:pathology; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*
chemical_list: D007375:Interleukin-1; D017493:Leukocyte Common Antigens; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1; D001973:Bromodeoxyuridine