Foam cell-derived 4-hydroxynonenal induces endothelial cell senescence in a TXNIP-dependent manner

Riahi, Yael and Kaiser, Nurit and Cohen, Guy and Abd-Elrahman, Ihab and Blum, Galia and Shapira, Oz M. and Koler, Tomer and Simionescu, Maya and Sima, Anca V. and Žarković, Neven and Žarković, Kamelija and Orioli, Marica and Aldini, Giancarlo and Cerasi, Erol and Leibowitz, Gil and Sasson, Shlomo (2015) Foam cell-derived 4-hydroxynonenal induces endothelial cell senescence in a TXNIP-dependent manner. Journal of Cellular and Molecular Medicine, 19 (8). pp. 1887-99. ISSN 1582-1838

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Abstract

Vascular endothelial cell (VEC) senescence is considered an early event in the development of atherosclerotic lesions. Stressful stimuli, in particular oxidative stress, have been linked to premature senescence in the vasculature. Foam cells are a major source of reactive oxygen species and may play a role in the induction of VEC senescence; hence, we investigated their involvement in the induction of VEC senescence in a co-culture transwell system. Primary bovine aortic endothelial cells, exposed to the secretome of THP-1 monocyte-derived foam cells, were analysed for the induction of senescence. Senescence associated β-galactosidase activity and the expression of p16 and p21 were increased, whereas phosphorylated retinoblastoma protein was reduced. This senescent phenotype was mediated by 4-hydroxnonenal (4-HNE), a lipid peroxidation product secreted from foam cells; scavenging of 4-HNE in the co-culture medium blunted this effect. Furthermore, both foam cells and 4-HNE increased the expression of the pro-oxidant thioredoxin-interacting protein (TXNIP). Molecular manipulation of TXNIP expression confirmed its involvement in foam cell-induced senescence. Previous studies showed that peroxisome proliferator-activated receptor (PPAR)δ was activated by 4-hydroalkenals, such as 4-HNE. Pharmacological interventions supported the involvement of the 4-HNE-PPARδ axis in the induction of TXNIP and VEC senescence. The association of TXNIP with VEC senescence was further supported by immunofluorescent staining of human carotid plaques in which the expression of both TXNIP and p21 was augmented in endothelial cells. Collectively, these findings suggest that foam cell-released 4-HNE activates PPARδ in VEC, leading to increased TXNIP expression and consequently to senescence.

Item Type: Article
Additional Information: © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
MeSH: Aldehydes/pharmacology ; Animals ; Biomarkers/metabolism ; Carrier Proteins/metabolism ; Cattle ; Cell Aging/drug effects ; Cell Line ; Coculture Techniques ; Endothelial Cells/cytology ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Fluorescent Antibody Technique ; Foam Cells/cytology ; Foam Cells/drug effects ; Foam Cells/metabolism ; Free Radical Scavengers/pharmacology ; Humans ; Lipid Peroxidation/drug effects ; Models, Biological ; PPAR delta/metabolism ; Plaque, Atherosclerotic/metabolism ; Plaque, Atherosclerotic/pathology
Departments: Katedra za patologiju
Depositing User: Marijan Šember
Status: Published
Creators:
CreatorsEmail
Riahi, YaelUNSPECIFIED
Kaiser, NuritUNSPECIFIED
Cohen, GuyUNSPECIFIED
Abd-Elrahman, IhabUNSPECIFIED
Blum, GaliaUNSPECIFIED
Shapira, Oz M.UNSPECIFIED
Koler, TomerUNSPECIFIED
Simionescu, MayaUNSPECIFIED
Sima, Anca V.UNSPECIFIED
Žarković, NevenUNSPECIFIED
Žarković, KamelijaUNSPECIFIED
Orioli, MaricaUNSPECIFIED
Aldini, GiancarloUNSPECIFIED
Cerasi, ErolUNSPECIFIED
Leibowitz, GilUNSPECIFIED
Sasson, ShlomoUNSPECIFIED
Date: August 2015
Date Deposited: 31 Mar 2016 12:10
Last Modified: 31 Mar 2016 12:10
Subjects: /
Related URLs:
URI: http://medlib.mef.hr/id/eprint/2567

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