Leukocyte cathepsin S is a potent regulator of both cell and matrix turnover in advanced atherosclerosis.
OBJECTIVE
A dysbalance of proteases and their inhibitors is instrumental in remodeling of atherosclerotic plaques. One of the proteases implicated in matrix degradation is cathepsin-S (CatS). To address its role in advanced lesion composition, we generated chimeric LDLr(-/-) mice deficient in leukocyte CatS by transplantation with CatS(-/-)xLDLr(-/-) or with LDLr(-/-) bone marrow and administered a high-fat diet.


RESULTS
No difference in aortic root lesion size could be detected between CatS(+/+) and CatS(-/-) chimeras. However, leukocyte CatS deficiency markedly changed plaque morphology and led to a dramatic reduction in necrotic core area by 77% and an abundance of large foam cells. Plaques of CatS(-/-) chimeras contained 17% more macrophages, 62% less SMCs, and 33% less intimal collagen. The latter two could be explained by a reduced number of elastic lamina fractures. Moreover, macrophage apoptosis was reduced by 60% with CatS deficiency. In vitro, CatS was found to be involved in cholesterol metabolism and in macrophage apoptosis in a collagen and fibronectin matrix.


CONCLUSIONS
Leukocyte CatS deficiency results in considerably altered plaque morphology, with smaller necrotic cores, reduced apoptosis, and decreased SMC content and collagen deposition and may thus be critical in plaque stability.
de Nooijer
R
R
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Leiden, The Netherlands.
Bot
I
I
von der Thüsen
J H
JH
Leeuwenburgh
M A
MA
Overkleeft
H S
HS
Kraaijeveld
A O
AO
Dorland
R
R
van Santbrink
P J
PJ
van Heiningen
S H
SH
Westra
M M
MM
Kovanen
P T
PT
Jukema
J W
JW
van der Wall
E E
EE
van Berkel
Th J C
TJ
Shi
G P
GP
Biessen
E A L
EA
D000818:Animals; D001011:Aorta / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D017209:Apoptosis; D050197:Atherosclerosis / Q000201:enzymology* / Q000209:etiology / Q000276:immunology / Q000473:pathology; D016026:Bone Marrow Transplantation; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D004547:Elastic Tissue / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005487:Foam Cells / Q000201:enzymology; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009336:Necrosis; D011480:Protease Inhibitors / Q000494:pharmacology; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D018183:Transplantation Chimera
D011480:Protease Inhibitors; D011973:Receptors, LDL; D003094:Collagen; D002784:Cholesterol; D002403:Cathepsins; C028217:cathepsin S