Pharmacological inhibition of Notch signaling regresses pre-established abdominal aortic aneurysm

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dc.contributor.authorSharma, Neekunen_ZA
dc.contributor.authorDev, Rishabhen_ZA
dc.contributor.authorRuiz-Rosado, Juan de Diosen_ZA
dc.contributor.authorPartida-Sanchez, Santiagoen_ZA
dc.contributor.authorGuerau-de-Arellano, Mireiaen_ZA
dc.contributor.authorDhakal, Pramoden_ZA
dc.contributor.authorKuivaniemi, Helenaen_ZA
dc.contributor.authorHans, Chetan P.en_ZA
dc.date.accessioned2021-11-09T07:31:27Z
dc.date.available2021-11-09T07:31:27Z
dc.date.issued2019-09-17
dc.descriptionCITATION: Sharma, N. et al. 2019. Pharmacological inhibition of Notch signaling regresses pre-established abdominal aortic aneurysm. Scientific Reports, 9. doi:10.1038/s41598-019-49682-0
dc.descriptionThe original publication is available at https://www.nature.com/srep/
dc.description.abstractENGLISH ABSTRACT: Abdominal aortic aneurysm (AAA) is characterized by transmural infiltration of myeloid cells at the vascular injury site. Previously, we reported preventive effects of Notch deficiency on the development of AAA by reduction of infiltrating myeloid cells. In this study, we examined if Notch inhibition attenuates the progression of pre-established AAA and potential implications. Pharmacological Notch inhibitor (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester; DAPT) was administered subcutaneously three times a week starting at day 28 of angiotensin II (AngII) infusion. Progressive increase in pulse wave velocity (PWV), maximal intra-luminal diameter (MILD) and maximal external aortic diameter (MEAD) were observed at day 56 of the AngII. DAPT prevented such increase in MILD, PWV and MEAD (P < 0.01). Histologically, the aortae of DAPT-treated Apoe−/− mice had significant reduction in inflammatory response and elastin fragmentation. Naked collagen microfibrils and weaker banded structure observed in the aortae of Apoe−/− mice in response to AngII, were substantially diminished by DAPT. A significant decrease in the proteolytic activity in the aneurysmal tissues and vascular smooth muscle cells (vSMCs) was observed with DAPT (P < 0.01). In human and mouse AAA tissues, increased immunoreactivity of activated Notch signaling correlated strongly with CD38 expression (R2 = 0.61). Collectively, we propose inhibition of Notch signaling as a potential therapeutic target for AAA progression.en_ZA
dc.description.versionPublisher’s version
dc.format.extent13 pagesen_ZA
dc.identifier.citationSharma, N. et al. 2019. Pharmacological inhibition of Notch signaling regresses pre-established abdominal aortic aneurysm. Scientific Reports, 9. doi:10.1038/s41598-019-49682-0
dc.identifier.issn2045-2322 (online)
dc.identifier.otherdoi:10.1038/s41598-019-49682-0
dc.identifier.urihttp://hdl.handle.net/10019.1/123396
dc.language.isoen_ZAen_ZA
dc.publisherNature Researchen_ZA
dc.rights.holderAuthors retain copyrighten_ZA
dc.subjectNotchen_ZA
dc.subjectAbdominal aneurysmen_ZA
dc.subjectAbdominal aortaen_ZA
dc.subjectProtease inhibitorsen_ZA
dc.titlePharmacological inhibition of Notch signaling regresses pre-established abdominal aortic aneurysmen_ZA
dc.typeArticleen_ZA
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