TY - JOUR
T1 - Pharmacological Inhibition of Cathepsin S Suppresses Abdominal Aortic Aneurysm in Mice
AU - Lai, Chao Han
AU - Chang, Jang Yang
AU - Wang, Kuan Chieh
AU - Lee, Fang Tzu
AU - Wu, Hua Lin
AU - Cheng, Tsung Lin
N1 - Funding Information:
This study is supported by grants from the Ministry of Science and Technology (MOST 105?2314-B-006?058-MY2 to CHL), Executive Yuan, Taiwan and a grant from National Cheng Kung University Hospital, Tainan, Taiwan (NCKUH-10605010 to CHL).
Funding Information:
This study is supported by grants from the Ministry of Science and Technology (MOST 105–2314-B-006–058-MY2 to CHL), Executive Yuan, Taiwan and a grant from National Cheng Kung University Hospital , Tainan, Taiwan (NCKUH- 10605010 to CHL).
Publisher Copyright:
© 2020 European Society for Vascular Surgery
PY - 2020/6
Y1 - 2020/6
N2 - 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 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.
AB - 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 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.
KW - Abdominal aortic aneurysm (AAA)
KW - Cathepsin S
KW - Cathepsin S inhibitor
KW - Elastin fragmentation
KW - Extracellular matrix
KW - Pharmacological treatment
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U2 - 10.1016/j.ejvs.2020.01.008
DO - 10.1016/j.ejvs.2020.01.008
M3 - Article
C2 - 32033870
AN - SCOPUS:85078825336
SN - 1078-5884
VL - 59
SP - 990
EP - 999
JO - European Journal of Vascular and Endovascular Surgery
JF - European Journal of Vascular and Endovascular Surgery
IS - 6
ER -