Sukhova Galina K, Zhang Yaou, Pan Jie-Hong, Wada Youichiro, Yamamoto Takashi, Naito Makoto, Kodama Tatsuhiko, Tsimikas Sotirios, Witztum Joseph L, Lu Michael L, Sakara Yasuhiko, Chin Michael T, Libby Peter, Shi Guo-Ping
The Leducq Center for Cardiovascular Research, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
J Clin Invest. 2003 Mar;111(6):897-906. doi: 10.1172/JCI14915.
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.
人类动脉粥样硬化病变中溶酶体半胱氨酸蛋白酶组织蛋白酶S（Cat S）过度表达，它是已知最强效的哺乳动物弹性蛋白酶之一。相比之下，与正常动脉相比，动脉粥样瘤中内源性Cat S抑制剂胱抑素C水平较低，提示这种蛋白酶参与动脉粥样硬化的发生。本研究通过将Cat S缺陷型（CatS(-/-)）小鼠与低密度脂蛋白受体缺陷型（LDLR(-/-)）小鼠杂交，直接验证了这一假说，后者在高胆固醇饮食条件下会发生动脉粥样硬化。与LDLR(-/-)小鼠相比，双敲除小鼠（CatS(-/-)LDLR(-/-)）的动脉粥样硬化明显减轻，从斑块大小（斑块面积和内膜增厚）和发展阶段可以看出。这些小鼠内膜巨噬细胞、脂质、平滑肌细胞、胶原蛋白、CD4(+) T淋巴细胞的含量以及干扰素-γ水平也显著降低。CatS(-/-)LDLR(-/-)单核细胞在内皮下基底膜迁移方面受损，CatS(-/-)LDLR(-/-)小鼠的主动脉弹性膜得以保留。这些发现确立了Cat S在动脉粥样硬化发生中的关键作用。
