Pharmacological inhibition of Notch signaling regresses pre-established abdominal aortic aneurysm
Date
2019-09-17
Journal Title
Journal ISSN
Volume Title
Publisher
Nature Research
Abstract
ENGLISH 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.
Description
CITATION: 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
The original publication is available at https://www.nature.com/srep/
The original publication is available at https://www.nature.com/srep/
Keywords
Notch, Abdominal aneurysm, Abdominal aorta, Protease inhibitors
Citation
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