The Key Laboratory of Remodeling-related Cardiovascular Diseases, Beijing An Zhen Hospital, Capital Medical University, Ministry of Education, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing 100029, China.
Cardiovasc Res. 2012 Dec 1;96(3):401-10. doi: 10.1093/cvr/cvs263. Epub 2012 Aug 7.
Abdominal aortic aneurysm (AAA) is characterized by extensive aortic wall matrix degradation that contributes to the remodelling and eventual rupture of the arterial wall. Elastinolytic cathepsin S (Cat S) is highly expressed in human aneurysmal lesions, but whether it contributes to the pathogenesis of AAA remains unknown.
AAAs were induced in apolipoprotein E (ApoE) and Cat S compound mutant (Apoe(-/-)Ctss(-/-)) mice and in ApoE-deficient Cat S wild-type littermates (Apoe(-/-)Ctss(+/+)) by chronic angiotensin II infusion, and AAA lesions were analysed after 28 days. We found that Cat S expression increased significantly in mouse AAA lesions. The AAA incidence in Apoe(-/-)Ctss(-/-) mice was much lower than that in Apoe(-/-)Ctss(+/+) mice (10 vs. 80%). Cat S deficiency significantly reduced external and luminal abdominal aortic diameters, medial elastin fragmentation, and adventitia collagen content. Cat S deficiency reduced aortic lesion expression and the activity of matrix metalloproteinase (MMP)-2, MMP-9, and Cat K, but not the activity of other major cathepsins, such as Cat B and Cat L. Absence of Cat S significantly reduced AAA lesion media smooth muscle cell (SMC) apoptosis, lesion adventitia microvessel content, and inflammatory cell accumulation and proliferation. In vitro studies proved that Cat S helps promote SMC apoptosis, angiogenesis, monocyte and T-cell transmigration, and T-cell proliferation--all of which are essential to AAA pathogenesis.
These data provide direct evidence that Cat S plays an important role in AAA formation and suggest that Cat S is a new therapeutic target for human AAA.
腹主动脉瘤（AAA）的特征是广泛的主动脉壁基质降解，导致动脉壁重塑和最终破裂。弹性蛋白酶 Cat S（Cat S）在人类动脉瘤病变中高度表达，但它是否有助于 AAA 的发病机制尚不清楚。
通过慢性血管紧张素 II 输注在载脂蛋白 E（ApoE）和 Cat S 复合突变体（Apoe(-/-)Ctss(-/-)）小鼠和 ApoE 缺陷型 Cat S 野生型同窝仔鼠（Apoe(-/-)Ctss(+/+)）中诱导 AAA，并在 28 天后分析 AAA 病变。我们发现 Cat S 表达在小鼠 AAA 病变中显著增加。Apoe(-/-)Ctss(-/-)小鼠的 AAA 发生率明显低于 Apoe(-/-)Ctss(+/+)小鼠（10% vs. 80%）。Cat S 缺乏显著降低了腹主动脉外径和内腔直径、中膜弹性蛋白碎片化和外膜胶原含量。Cat S 缺乏降低了主动脉病变的表达和基质金属蛋白酶（MMP）-2、MMP-9 和 Cat K 的活性，但不影响其他主要组织蛋白酶的活性，如 Cat B 和 Cat L。Cat S 缺失显著降低了 AAA 病变中膜平滑肌细胞（SMC）凋亡、病变外膜微血管含量、炎症细胞积聚和增殖。体外研究证明 Cat S 有助于促进 SMC 凋亡、血管生成、单核细胞和 T 细胞迁移以及 T 细胞增殖——所有这些都是 AAA 发病机制所必需的。
这些数据提供了直接证据，表明 Cat S 在 AAA 的形成中起重要作用，并表明 Cat S 是人类 AAA 的一个新的治疗靶点。
