Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Arterioscler Thromb Vasc Biol. 2012 Jan;32(1):15-23. doi: 10.1161/ATVBAHA.111.235002. Epub 2011 Aug 4.
Cathepsin K (CatK) is one of the most potent mammalian elastases. We have previously shown increased expression of CatK in human abdominal aortic aneurysm (AAA) lesions. Whether this protease participates directly in AAA formation, however, remains unknown.
Mouse experimental AAA was induced with aortic perfusion of a porcine pancreatic elastase. Using this experimental model, we demonstrated that absence of CatK prevented AAA formation in mice 14 days postperfusion. CatK deficiency significantly reduced lesion CD4(+) T-cell content, total lesion and medial cell proliferation and apoptosis, medial smooth muscle cell (SMC) loss, elastinolytic CatL and CatS expression, and elastin fragmentation, but it did not affect AAA lesion Mac-3(+) macrophage accumulation or CD31(+) microvessel numbers. In vitro studies revealed that CatK contributed importantly to CD4(+) T-cell proliferation, SMC apoptosis, and other cysteinyl cathepsin and matrix metalloproteinase expression and activities in SMCs and endothelial cells but played negligible roles in microvessel growth and monocyte migration. AAA lesions from CatK-deficient mice showed reduced elastinolytic cathepsin activities compared with those from wild-type control mice.
This study demonstrates that CatK plays an essential role in AAA formation by promoting T-cell proliferation, vascular SMC apoptosis, and elastin degradation and by affecting vascular cell protease expression and activities.
组织蛋白酶 K（CatK）是最有效的哺乳动物弹性蛋白酶之一。我们之前已经表明，CatK 在人类腹主动脉瘤（AAA）病变中的表达增加。然而，这种蛋白酶是否直接参与 AAA 的形成尚不清楚。
使用猪胰弹性蛋白酶对主动脉进行灌注，诱导小鼠实验性 AAA。使用这种实验模型，我们证明 CatK 缺失可预防灌注后 14 天的小鼠发生 AAA。CatK 缺乏显著降低了病变中的 CD4(+)T 细胞含量、总病变和中膜细胞增殖和凋亡、中膜平滑肌细胞（SMC）丢失、弹性蛋白酶 CatL 和 CatS 的表达以及弹性蛋白片段化，但不影响 AAA 病变中 Mac-3(+)巨噬细胞的积累或 CD31(+)微血管数量。体外研究表明，CatK 对 CD4(+)T 细胞增殖、SMC 凋亡以及 SMC 和内皮细胞中其他半胱氨酸组织蛋白酶和基质金属蛋白酶的表达和活性有重要贡献，但对微血管生长和单核细胞迁移的作用可以忽略不计。与野生型对照小鼠相比，CatK 缺陷型小鼠的 AAA 病变中的弹性蛋白酶活性降低。
本研究表明，CatK 通过促进 T 细胞增殖、血管 SMC 凋亡和弹性蛋白降解，并通过影响血管细胞蛋白酶的表达和活性，在 AAA 的形成中起着重要作用。
