Pharmacological Inhibition of Cathepsin S Suppresses Abdominal Aortic Aneurysm in Mice.
Eur J Vasc Endovasc Surg
; 59(6): 990-999, 2020 Jun.
Article
en En
| MEDLINE
| ID: mdl-32033870
ABSTRACT
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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Aorta Abdominal
/
Catepsinas
/
Aneurisma de la Aorta Abdominal
/
Amidas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Eur J Vasc Endovasc Surg
Asunto de la revista:
ANGIOLOGIA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Taiwán