EXPRESSION OF THE ELASTOLYTIC CATHEPSIN-S AND CATHEPSIN-K IN HUMAN ATHEROMA AND REGULATION OF THEIR PRODUCTION IN SMOOTH-MUSCLE CELLS

Formation of the atherosclerotic intima must involve altered metabolis m of the elastin-rich arterial extracellular matrix. Proteases potenti ally involved in these processes remain unclear. This study examined t he expression of the potent elastases cathepsins S and K in human athe roma. Normal arteries contained little or no cathepsin K or S. In cont rast, macrophages in atheroma contained abundant immunoreactive cathep sins K and S, Intimal smooth muscle cells (SIMC), especially cells app earing to traverse the internal elastic laminae, also contained these enzymes. Extracts of atheromatous tissues had approximately twofold gr eater elastase-specific activity than extracts of uninvolved arteries, mostly due to cysteine proteases. Cultured human SMC displayed no imm unoreactive cathepsins K and S and exhibited little or no elastolytic activity when incubated with insoluble elastin. SMC stimulated with th e atheroma-associated cytokines IL-1 beta or IFN-gamma secreted active cathepsin S and degraded substantial insoluble elastin (15-20 mu g/10 (6) cells/24 h). A selective inhibitor of cathepsin S blocked > 80% of this elastolytic activity. The presence of cathepsins K and S at site s of vascular matrix remodeling and the ability of SMC and macrophages to use these enzymes to degrade elastin supports a role for elastolyt ic cathepsins in vessel wall remodeling and identifies novel therapeut ic targets in regulating plaque stability.