Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice
Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice
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DOI：
10.1172/jci200314915
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发表时间：
2003-03-01
影响因子：
15.9
通讯作者：
Shi, GP
中科院分区：
文献类型：
--
作者：
Sukhova, GK;Zhang, Y;Shi, GP
人类动脉粥样硬化病变过度表达溶酶体半胱氨酸蛋白酶组织蛋白酶S（Cat S），它是已知的最强的哺乳动物弹性蛋白酶之一。相比之下，与正常动脉相比，动脉粥样斑块中内源性Cat S抑制剂胱抑素C水平较低，这表明该蛋白酶参与了动脉粥样硬化的形成。本研究通过将组织蛋白酶S缺陷型（CatS(-/-)）小鼠与在高胆固醇饮食下会发生动脉粥样硬化的低密度脂蛋白受体缺陷型（LDLR -/-）小鼠杂交，直接验证了这一假设。与LDLR -/-小鼠相比，双敲除小鼠（CatS(-/-)LDLR(-/-)）的动脉粥样硬化明显减轻，这从斑块大小（斑块面积和内膜增厚）以及发展阶段可以看出。这些小鼠内膜中的巨噬细胞、脂质、平滑肌细胞、胶原蛋白、CD4(+) T淋巴细胞含量以及干扰素 -γ水平也显著降低。CatS(-/-)LDLR(-/-)单核细胞显示出内皮下基底膜迁移受损，并且CatS(-/-)LDLR(-/-)小鼠的主动脉弹性膜得以保留。这些发现确立了组织蛋白酶S在动脉粥样硬化形成中的关键作用。
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.