DAPT, a potent Notch inhibitor regresses actively growing abdominal aortic aneurysm via divergent pathways.

Autor:	Hans CP; Department of Cardiovascular Medicine, University of Missouri, Columbia, MO, U.S.A.; Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, U.S.A.; Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, U.S.A., Sharma N; Department of Cardiovascular Medicine, University of Missouri, Columbia, MO, U.S.A.; Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, U.S.A., Dev R; Department of Cardiovascular Medicine, University of Missouri, Columbia, MO, U.S.A.; Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, U.S.A., Blain JM; Department of Biomedical Engineering, The Ohio State University, Columbus, OH, U.S.A., Tonniges J; Biophysics Graduate Program, The Ohio State University, Columbus, OH, U.S.A., Agarwal G; Department of Biomedical Engineering, The Ohio State University, Columbus, OH, U.S.A.; Biophysics Graduate Program, The Ohio State University, Columbus, OH, U.S.A.
Jazyk:	angličtina
Zdroj:	Clinical science (London, England : 1979) [Clin Sci (Lond)] 2020 Jun 26; Vol. 134 (12), pp. 1555-1572.
DOI:	10.1042/CS20200456
Abstrakt:	Abdominal aortic aneurysm (AAA) is a localized pathological dilation of the aorta exceeding the normal diameter (∼20 mm) by more than 50% of its original size (≥30 mm), accounting for approximately 150000-200000 deaths worldwide per year. We previously reported that Notch inhibition does not decrease the size of pre-established AAA at late stage of the disease. Here, we examined whether a potent pharmacologic inhibitor of Notch signaling (DAPT (N-[N-(3,5-Difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester)), regresses an actively growing AAA. In a mouse model of an aneurysm (Apoe-/- mice; n=44); DAPT (n=17) or vehicle (n=17) was randomly administered at day 14 of angiotensin II (AngII; 1 µg/min/kg), three times a week and mice were killed on day 42. Progressive increase in aortic stiffness and maximal intraluminal diameter (MILD) was observed in the AngII + vehicle group, which was significantly prevented by DAPT (P<0.01). The regression of aneurysm with DAPT was associated with reduced F4/80+Cd68+ (cluster of differentiation 68) inflammatory macrophages. DAPT improved structural integrity of aorta by reducing collagen fibrils abnormality and restoring their diameter. Mechanistically, C-C chemokine receptor type 7 (Ccr7)+F4/80- dendritic cells (DCs), implicated in the regression of aneurysm, were increased in the aorta of DAPT-treated mice. In the macrophages stimulated with AngII or lipopolysaccharide (LPS), DAPT reverted the expression of pro-inflammatory genes Il6 and Il12 back to baseline within 6 h compared with vehicle (P<0.05). DAPT also significantly increased the expression of anti-inflammatory genes, including c-Myc, Egr2, and Arg1 at 12-24 h in the LPS-stimulated macrophages (P<0.05). Overall, these regressive effects of Notch signaling inhibitor emphasize its therapeutic implications to prevent the progression of active AAAs. (© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
Databáze:	MEDLINE
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