ACTIVATION OF MATRIX-DEGRADING METALLOPROTEINASES BY MAST-CELL PROTEASES IN ATHEROSCLEROTIC PLAQUES

Recent studies suggest that mast cell-derived neutral proteases can ac tivate matrix-degrading metalloproteinases (MMPs). We have investigate d the role of the mast cell proteases tryptase and chymase in the acti vation of MMPs in human carotid endarterectomy specimens (atherosclero tic, n=32) and postmortem carotid arteries (control, n=17). In vitro d egranulation of mast cells in atherosclerotic carotid arteries by comp ound 48/80 caused a significant increase in MMP activity. Addition of the nonselective tryptase inhibitor antipain, the specific trypsinlike protease inhibitor 4-amidinophenylmethanesulfonyl fluoride, and the c hymase inhibitor chymostatin reduced this increase in MMP activity by 30+/-6%, 23+/-6%, and 9+/-2%, respectively. Immunocytochemistry identi fied significantly higher numbers of tryptase-containing cells (mast c ells) and cells expressing MMP-1 and MMP-3 in the ''shoulder'' regions of atherosclerotic artery lesions compared with the tunica media of c ontrol arteries. Dual immunocytochemistry showed collocation of MMP-1 and MMP-3 with mast cells in the shoulder regions. Degranulation was o bserved in 78+/-5% (mean+/-SEM) of mast cells in this area, whereas no nactivated mast cells were observed in all other areas. In situ zymogr aphy revealed caseinolytic and gelatinolytic activity in these areas. In conclusion, in vitro mast cell degranulation, which releases mast c ell proteases, in carotid arteries increases MMP activity. Furthermore , elevated MMP-1 and MMP-3 expression is collocated with increased num bers of degranulated mast cells and with greater MMP activity in the s houlder regions of atherosclerotic plaques. Activation of MMPs by mast cell-derived proteases may be an important mechanism in atherosclerot ic plaque destabilization.