Deficiency of cathepsin S reduces atherosclerosis in LDL receptor–deficient mice
Galina K. Sukhova, … , Peter Libby, Guo-Ping Shi
Galina K. Sukhova, … , Peter Libby, Guo-Ping Shi
Published March 15, 2003
Citation Information: J Clin Invest. 2003;111(6):897-906. https://doi.org/10.1172/JCI14915.
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Article Vascular biology

Deficiency of cathepsin S reduces atherosclerosis in LDL receptor–deficient mice

Abstract

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-γ. 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.

Authors

Galina K. Sukhova, Yaou Zhang, Jie-Hong Pan, Youichiro Wada, Takashi Yamamoto, Makoto Naito, Tatsuhiko Kodama, Sotirios Tsimikas, Joseph L. Witztum, Michael L. Lu, Yasuhiko Sakara, Michael T. Chin, Peter Libby, Guo-Ping Shi

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Figure 1

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Cat S deficiency reduces the area of aortic lipid accumulation. After co...
Cat S deficiency reduces the area of aortic lipid accumulation. After consuming the atherogenic diet for 12 or 26 weeks, both CatS–/–LDLR–/– and LDLR–/– mouse abdominal aortas were isolated and stained for lipid deposition with oil red O. The left panels show representative specimens used to calculate the percentages of oil red O–positive areas shown in the bar graphs on the right. No aortic lipid deposition was seen in mice fed an atherogenic diet for 8 weeks (data not shown).