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Titel: The metalloproteinase ADAM15 is upregulated by shear stress and promotes survival of endothelial cells
VerfasserIn: Babendreyer, Aaron
Molls, Lisa
Simons, Indra M.
Dreymueller, Daniela
Biller, Kristina
Jahr, Holger
Denecke, Bernd
Boon, Reinier A.
Bette, Sebastian
Schnakenberg, Uwe
Ludwig, Andreas
Sprache: Englisch
Titel: Journal of Molecular and Cellular Cardiology
Bandnummer: 134
Seiten: 51-61
Verlag/Plattform: Elsevier
Erscheinungsjahr: 2019
Freie Schlagwörter: Shear stress
Blood flow
Endothelium
Metalloproteinase
Cell death
Transcriptional regulation
Vascular inflammation
DDC-Sachgruppe: 610 Medizin, Gesundheit
Dokumenttyp: Journalartikel / Zeitschriftenartikel
Abstract: Reduced shear stress resulting from disturbed blood flow can impair endothelial integrity and drive the development of vascular inflammatory lesions. Metalloproteinases of the ADAM family have been implicated in the regulation of cell survival and inflammatory responses. Here we investigate the mechanism and function of ADAM15 upregulation in primary flow cultured endothelial cells. Transcriptomic analysis indicated that within the ADAM family ADAM15 mRNA is most prominently upregulated (4-fold) when endothelial cells are exposed to physiologic shear stress. This induction was confirmed in venous, arterial and microvascular endothelial cells and is associated with increased presence of ADAM15 protein in the cell lysates (5.6-fold) and on the surface (3.1-fold). The ADAM15 promoter contains several consensus sites for the transcription factor KLF2 which is also upregulated by shear stress. Induction of endothelial KLF2 by simvastatin treatment is associated with ADAM15 upregulation (1.8-fold) which is suppressed by counteracting simvastatin with geranylgeranyl pyrophosphate. KLF2 overexpression promotes ADAM15 expression (2.1-fold) under static conditions whereas KLF2 siRNA knockdown prevents ADAM15 induction by shear stress. Functionally, ADAM15 promotes survival of endothelial cells challenged by growth factor depletion or TNF stimulation as shown by ADAM15 shRNA knockdown (1.6-fold). Exposure to shear stress increases endothelial survival while additional knockdown of ADAM15 reduces survival (6.7-fold) under flow conditions. Thus, physiologic shear stress resulting from laminar flow promotes KLF2 induced ADAM15 expression which contributes to endothelial survival. The absence of ADAM15 at low shear stress or static conditions may therefore lead to increased endothelial damage and promote vascular inflammation.
DOI der Erstveröffentlichung: 10.1016/j.yjmcc.2019.06.017
URL der Erstveröffentlichung: https://www.sciencedirect.com/science/article/abs/pii/S0022282819301452
Link zu diesem Datensatz: urn:nbn:de:bsz:291--ds-371701
hdl:20.500.11880/33726
http://dx.doi.org/10.22028/D291-37170
ISSN: 0022-2828
Datum des Eintrags: 7-Sep-2022
Fakultät: M - Medizinische Fakultät
Fachrichtung: M - Experimentelle und Klinische Pharmakologie und Toxikologie
Professur: M - Jun.-Prof. Dr. Daniela Yildiz
Sammlung:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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