Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 111, Issue 6, Pages 897-906Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI200314915
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Funding
- NHLBI NIH HHS [HL-34636, R01 HL034636, R37 HL034636, R01 HL060942, HL-60942, HL-56985, P50 HL056985] Funding Source: Medline
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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.
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