Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells.
Formation of the atherosclerotic intima must involve altered metabolism of the elastin-rich arterial extracellular matrix. Proteases potentially involved in these processes remain unclear. This study examined the expression of the potent elastases cathepsins S and K in human atheroma. Normal arteries contained little or no cathepsin K or S. In contrast, macrophages in atheroma contained abundant immunoreactive cathepsins K and S. Intimal smooth muscle cells (SMC), especially cells appearing to traverse the internal elastic laminae, also contained these enzymes. Extracts of atheromatous tissues had approximately twofold greater elastase-specific activity than extracts of uninvolved arteries, mostly due to cysteine proteases. Cultured human SMC displayed no immunoreactive cathepsins K and S and exhibited little or no elastolytic activity when incubated with insoluble elastin. SMC stimulated with the atheroma-associated cytokines IL-1beta or IFN-gamma secreted active cathepsin S and degraded substantial insoluble elastin (15-20 microg/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 sites of vascular matrix remodeling and the ability of SMC and macrophages to use these enzymes to degrade elastin supports a role for elastolytic cathepsins in vessel wall remodeling and identifies novel therapeutic targets in regulating plaque stability.
Sukhova
G K
GK
Brigham and Women's Hospital, Vascular Medicine and Atherosclerosis Unit and Cardiovascular and Respiratory Divisions, Department of Medicine, Boston, Massachusetts 02115, USA.
Shi
G P
GP
Simon
D I
DI
Chapman
H A
HA
Libby
P
P
D001161:Arteriosclerosis / Q000201:enzymology* / Q000235:genetics; D016893:Carotid Stenosis / Q000201:enzymology / Q000235:genetics; D056657:Cathepsin K; D002403:Cathepsins / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured; D003327:Coronary Disease / Q000201:enzymology / Q000235:genetics; D004549:Elastin / Q000378:metabolism*; D004790:Enzyme Induction; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017539:Tunica Intima / Q000166:cytology / Q000378:metabolism
D012333:RNA, Messenger; D007371:Interferon-gamma; D004549:Elastin; D002403:Cathepsins; C028217:cathepsin S; C534130:CTSK protein, human; D056657:Cathepsin K