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

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 inhibitio...

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Bibliographic Details
Published in:Scientific reports 2019-09, Vol.9 (1), p.13458-13, Article 13458
Main Authors: Sharma, Neekun, Dev, Rishabh, Ruiz-Rosado, Juan de Dios, Partida-Sanchez, Santiago, Guerau-de-Arellano, Mireia, Dhakal, Pramod, Kuivaniemi, Helena, Hans, Chetan P
Format: Article
Language:English
Subjects:
ADP-ribosyl Cyclase 1 - metabolism
Aneurysms
Angiotensin
Angiotensin II
Angiotensin II - adverse effects
Animals
Aorta - drug effects
Aorta - metabolism
Aortic Aneurysm, Abdominal - chemically induced
Aortic Aneurysm, Abdominal - diagnostic imaging
Aortic Aneurysm, Abdominal - drug therapy
Aortic Aneurysm, Abdominal - metabolism
Aortic aneurysms
Apolipoprotein E
CD38 antigen
Cells, Cultured
Collagen
Collagen - metabolism
Cytokines - metabolism
Dipeptides - pharmacology
Disease Models, Animal
Elastin
Extracellular Matrix - drug effects
Extracellular Matrix - metabolism
Gene Expression Regulation - drug effects
Humans
Immunoreactivity
Inflammation
Male
Membrane Glycoproteins - metabolism
Mice
Microfibrils
Myeloid cells
Myocytes, Smooth Muscle - drug effects
Myocytes, Smooth Muscle - metabolism
Phenylglycine
Proteolysis
Receptors, Notch - antagonists & inhibitors
Receptors, Notch - metabolism
Signal Transduction - drug effects
Smooth muscle
Therapeutic applications
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Summary: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 
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-019-49682-0