组织蛋白酶 S 的药理学抑制可抑制小鼠的腹主动脉瘤。
Pharmacological Inhibition of Cathepsin S Suppresses Abdominal Aortic Aneurysm in Mice.
机构信息
Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Cardiovascular Research Centre, College of Medicine, National Cheng Kung University, Taiwan.
Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
出版信息
Eur J Vasc Endovasc Surg. 2020 Jun;59(6):990-999. doi: 10.1016/j.ejvs.2020.01.008. Epub 2020 Feb 4.
OBJECTIVE
Evidence suggests that cathepsin S (CTSS), a potent mammalian elastase, participates in abdominal aortic aneurysm (AAA) formation. This study examines the hypothesis that pharmacological inhibition of CTSS with an α-ketoamide based compound 6r might suppress AAA in mice.
METHODS
Experimental study of the CaCl induced AAA model in B6 mice and angiotensin II (AngII) infused AAA model in ApoE mice. The effects of intraperitoneal administration of 6r (25 mg/kg) and vehicle every three days since one day after AAA induction were evaluated at 28 days using CaCl induced (n = 12 per group) and AngII infused (n = 8 per group) models. Additionally, the effects of post-treatment with 6r and vehicle from seven days or 14 days after AAA induction were evaluated at 28 days using the CaCl induced model (n = 6 per group). Aortic samples were harvested for histological and biochemical analyses, including cathepsin levels, Verhoeff Van Gieson staining, TUNEL assay, and immunostaining for macrophages.
RESULTS
In the CaCl induced model, treatment with 6r suppressed aortic dilatation observed in vehicle treated controls (median: 0.58 vs. 0.92 mm; p < .001), along with reduced CTSS and cathepsin K (CTSK) levels (both p < .001), preserved elastin integrity (p < .001), fewer medial apoptotic cells (p = .012) and less macrophage infiltration (p = .041). In the AngII infused model, the aortic diameter was smaller in 6r treated mice than in vehicle treated controls (median: 0.95 vs. 1.84 mm; p = .047). The levels of CTSS (p < .001) and CTSK (p = .033) and the numbers of elastin breaks (p < .001), medial apoptotic cells (p < .001) and infiltrating macrophages (p = .030) were attenuated under 6r treatment. Finally, post-treatment with 6r from seven days (p = .046) or 14 days (p = .012) after AAA induction limited CaCl induced AAA.
CONCLUSION
Pharmacological inhibition of CTSS by 6r suppresses AAA formation in mice. Also, post-treatment with 6r retards mouse AAA progression. These findings provide proof of concept validation for CTSS as a potential therapeutic target in AAA.
目的
有证据表明，组织蛋白酶 S（CTSS）是一种强有力的哺乳动物弹性蛋白酶，参与了腹主动脉瘤（AAA）的形成。本研究旨在检验以下假设：用基于α-酮酰胺的化合物 6r 对 CTSS 进行药理学抑制可能会抑制小鼠的 AAA。
方法
在 B6 小鼠的 CaCl2 诱导 AAA 模型和 ApoE 小鼠的血管紧张素 II（AngII）输注 AAA 模型中进行实验性研究。用 CaCl2 诱导（每组 12 只）和 AngII 输注（每组 8 只）模型，从 AAA 诱导后 1 天开始，每 3 天腹腔注射 6r（25mg/kg）和载体，28 天后评估其效果。此外，用 CaCl2 诱导模型（每组 6 只），从 AAA 诱导后 7 天或 14 天开始，用 6r 和载体进行后期治疗，28 天后评估其效果。采集主动脉样本进行组织学和生化分析，包括组织蛋白酶水平、Verhoeff Van Gieson 染色、TUNEL 检测和巨噬细胞免疫染色。
结果
在 CaCl2 诱导的模型中，用 6r 治疗可抑制对照组载体处理的主动脉扩张（中位数：0.58 与 0.92mm；p<0.001），同时降低 CTSS 和组织蛋白酶 K（CTSK）水平（均 p<0.001），保持弹性蛋白完整性（p<0.001），减少中层凋亡细胞（p=0.012）和巨噬细胞浸润（p=0.041）。在 AngII 输注模型中，与载体处理的对照组相比，6r 处理的小鼠的主动脉直径较小（中位数：0.95 与 1.84mm；p=0.047）。6r 治疗可降低 CTSS（p<0.001）和 CTSK（p=0.033）水平，减少弹性蛋白断裂（p<0.001）、中层凋亡细胞（p<0.001）和浸润的巨噬细胞（p=0.030）数量。最后，从 AAA 诱导后 7 天（p=0.046）或 14 天（p=0.012）开始用 6r 进行后期治疗可限制 CaCl2 诱导的 AAA。
结论
用 6r 抑制 CTSS 的药理学作用可抑制小鼠的 AAA 形成。此外，用 6r 进行后期治疗可延缓小鼠 AAA 的进展。这些发现为 CTSS 作为 AAA 的潜在治疗靶点提供了概念验证。
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