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.
Brigham and Women's Hospital, Vascular Medicine and Atherosclerosis Unit and Cardiovascular and Respiratory Divisions, Department of Medicine, Boston, Massachusetts 02115, USA.
G K
GK
Sukhova
G P
GP
Shi
D I
DI
Simon
H A
HA
Chapman
P
P
Libby
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