國家衛生研究院 NHRI:Item 3990099045/12528
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    題名: Pharmacological inhibition of cathepsin S suppresses abdominal aortic aneurysm in mice
    作者: Lai, CH;Chang, JY;Wang, KC;Lee, FT;Wu, HL;Cheng, TL
    貢獻者: National Institute of Cancer Research
    摘要: 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 alpha-ketoamide based compound 6r might suppress AAA in mice. METHODS: Experimental study of the CaCl2 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 CaCl2 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 CaCl2 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 CaCl2 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 CaCl2 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.
    日期: 2020-06
    關聯: European Journal of Vascular and Endovascular Surgery. 2020 Jun;59(6):990-999.
    Link to: http://dx.doi.org/10.1016/j.ejvs.2020.01.008
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1078-5884&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000540216900028
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85078825336
    顯示於類別:[張俊彥] 期刊論文

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