title: Notch-dependent EMT is attenuated in patients with aortic aneurysm and bicuspid aortic valve.
abstract: Bicuspid aortic valve is the most common congenital heart malformation and the reasons for the aortopathies associated with bicuspid aortic valve remain unclear. NOTCH1 mutations are associated with bicuspid aortic valve and have been found in individuals with various left ventricular outflow tract abnormalities. Notch is a key signaling during cardiac valve formation that promotes the endothelial-to-mesenchymal transition. We address the role of Notch signaling in human aortic endothelial cells from patients with bicuspid aortic valve and aortic aneurysm. Aortic endothelial cells were isolated from tissue fragments of bicuspid aortic valve-associated thoracic aortic aneurysm patients and from healthy donors. Endothelial-to-mesenchymal transition was induced by activation of Notch signaling. Effectiveness of the transition was estimated by loss of endothelial and gain of mesenchymal markers by immunocytochemistry and qPCR. We show that aortic endothelial cells from the patients with aortic aneurysm and bicuspid aortic valve have down regulated Notch signaling and fail to activate Notch-dependent endothelial-to-mesenchymal transition in response to its stimulation by different Notch ligands. Our findings support the idea that bicuspid aortic valve and associated aortic aneurysm is associated with dysregulation of the entire Notch signaling pathway independently on the specific gene mutation.
authors.affiliation: Almazov Federal Medical Research Centre, Saint-Petersburg, Russia; University of Verona, Verona, Italy.
authors.forename: Aleksandra S
authors.initials: AS
authors.lastname: Kostina
authors.affiliation: Almazov Federal Medical Research Centre, Saint-Petersburg, Russia.
authors.forename: Vladimir Е
authors.initials: VЕ
authors.lastname: Uspensky
authors.affiliation: Almazov Federal Medical Research Centre, Saint-Petersburg, Russia; ITMO University, Institute of translational Medicine, St. Petersburg, Russia.
authors.forename: Olga B
authors.initials: OB
authors.lastname: Irtyuga
authors.affiliation: Almazov Federal Medical Research Centre, Saint-Petersburg, Russia.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Ignatieva
authors.affiliation: Almazov Federal Medical Research Centre, Saint-Petersburg, Russia.
authors.forename: Olga
authors.initials: O
authors.lastname: Freylikhman
authors.affiliation: Almazov Federal Medical Research Centre, Saint-Petersburg, Russia.
authors.forename: Natalia D
authors.initials: ND
authors.lastname: Gavriliuk
authors.affiliation: Almazov Federal Medical Research Centre, Saint-Petersburg, Russia.
authors.forename: Olga M
authors.initials: OM
authors.lastname: Moiseeva
authors.affiliation: Almazov Federal Medical Research Centre, Saint-Petersburg, Russia.
authors.forename: Sergey
authors.initials: S
authors.lastname: Zhuk
authors.affiliation: Institute of Cytology, Russian Academy of Sciences, Saint-Petersburg, Russia.
authors.forename: Alexey
authors.initials: A
authors.lastname: Tomilin
authors.affiliation: Almazov Federal Medical Research Centre, Saint-Petersburg, Russia; ITMO University, Institute of translational Medicine, St. Petersburg, Russia.
authors.forename: Аnna А
authors.initials: АА
authors.lastname: Kostareva
authors.affiliation: Almazov Federal Medical Research Centre, Saint-Petersburg, Russia; ITMO University, Institute of translational Medicine, St. Petersburg, Russia; Almazov Medical Research Centre, St. Petersburg State University, Saint-Petersburg, Russia. Electronic address: malashicheva_ab@almazovcentre.ru.
authors.forename: Anna B
authors.initials: AB
authors.lastname: Malashicheva
mesh_terms: D000328:Adult; D001014:Aortic Aneurysm / Q000378:metabolism* / Q000473:pathology; D001021:Aortic Valve / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D000082882:Bicuspid Aortic Valve Disease; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006349:Heart Valve Diseases / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051880:Receptors, Notch
keywords: Aorta; Endothelium; Signal transduction; Valves