Expression of HLA-DR antigen and smooth muscle cell differentiation markers by valvular fibroblasts in degenerative aortic stenosis

Department of Cardiology, Institution of Medicine, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden.

OBJECTIVES. This study was designed to analyze the functional characteristics of fibroblasts present in aortic valves with degenerative stenosis. BACKGROUND. Morphologic analysis of degenerative stenosis of tricuspid aortic valves has revealed an extensive interstitial fibrosis. METHODS. Stenotic aortic valves collected during aortic valve replacement and control valves collected at autopsy were fixed in formaldehyde, cryosectioned and stained with antibodies against leukocyte markers, HLA-DR and intracellular filaments. Fibroblasts isolated from stenotic valve and skin explants were grown in cell culture, and their proliferative activity was analyzed by cell counting and uptake of tritiated thymidine. RESULTS. In the stenotic valves nearly all interstitial cells expressed vimentin, and approximately 60% of the cells also expressed alpha-actin and desmin. HLA-DR was present on inflammatory cells as well as on one-third of the fibroblast-like cells in the interstitium. Macrophages were found in the interstitium and T lymphocytes close to calcium deposits and in subendothelial areas. In control valves, fibroblasts expressed vimentin but not alpha-actin or desmin. Few inflammatory cells were present in these valves, and HLA-DR expression was restricted to the endothelial surface. In culture, stenotic valve fibroblasts had a reduced ability to proliferate in serum and to activate DNA synthesis in response to growth factors compared with skin fibroblasts from the same patient. CONCLUSIONS. The observation that fibroblasts present in aortic valves with degenerative stenosis express smooth muscle cell characteristics and HLA-DR antigen and show signs of cellular senescence in vitro suggests that they are in a state of chronic activation similar to that observed in fibromatosis and scleroderma lesions.

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