Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis

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)- 1beta on MMP expression and cell proliferation in human aortic valves. Immunohistochemistry for leukocytes, IL-1beta 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-1beta and MMP-1. In control valves only scattered leukocytes, low staining for MMP-1 and no staining for IL-1beta were present. Double-label immunostaining localized IL-1beta expression mainly to leukocytesandMMP-1 expression to myofibroblasts. Stimulation of cultured human aortic valve myofibroblasts with IL-1beta lead to a time-dependently increased expression of MMP- I and MMP-2 by Western blotting and zymography, whereas MMP-9 remained unchanged. Cell proliferation was increased by IL-1beta as determined by bromodesoxyuridine incorporation. Thus, IL-1beta may regulate remodeling of the extracellular matrix in calcific AS. (C) 2003 Elsevier Ireland Ltd. All rights reserved.