Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice.
Human atherosclerotic lesions overexpress the lysosomal cysteine protease cathepsin S (Cat S), one of the most potent mammalian elastases known. In contrast, atheromata have low levels of the endogenous Cat S inhibitor cystatin C compared with normal arteries, suggesting involvement of this protease in atherogenesis. The present study tested this hypothesis directly by crossing Cat S-deficient (CatS(-/-)) mice with LDL receptor-deficient (LDLR(-/-)) mice that develop atherosclerosis on a high-cholesterol diet. Compared with LDLR(-/-) mice, double-knockout mice (CatS(-/-)LDLR(-/-)) developed significantly less atherosclerosis, as indicated by plaque size (plaque area and intimal thickening) and stage of development. These mice also had markedly reduced content of intimal macrophages, lipids, smooth muscle cells, collagen, CD4(+) T lymphocytes, and levels of IFN-gamma. CatS(-/-)LDLR(-/-) monocytes showed impaired subendothelial basement membrane transmigration, and aortas from CatS(-/-)LDLR(-/-) mice had preserved elastic laminae. These findings establish a pivotal role for Cat S in atherogenesis.
Sukhova
Galina K
GK
The Leducq Center for Cardiovascular Research, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Zhang
Yaou
Y
Pan
Jie-Hong
JH
Wada
Youichiro
Y
Yamamoto
Takashi
T
Naito
Makoto
M
Kodama
Tatsuhiko
T
Tsimikas
Sotirios
S
Witztum
Joseph L
JL
Lu
Michael L
ML
Sakara
Yasuhiko
Y
Chin
Michael T
MT
Libby
Peter
P
Shi
Guo-Ping
GP
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology* / Q000473:pathology; D002403:Cathepsins / Q000502:physiology*; D002465:Cell Movement; D003094:Collagen / Q000032:analysis; D004549:Elastin / Q000378:metabolism; D007962:Leukocytes / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000166:cytology; D011817:Rabbits; D011973:Receptors, LDL / Q000502:physiology*
D011973:Receptors, LDL; D003094:Collagen; D004549:Elastin; D002403:Cathepsins; C028217:cathepsin S