title: Foam cell-derived 4-hydroxynonenal induces endothelial cell senescence in a TXNIP-dependent manner.
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.
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.|Endocrinology and Metabolism Service, Department of Medicine, The Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Riahi
authors.affiliation: Endocrinology and Metabolism Service, Department of Medicine, The Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Nurit
authors.initials: N
authors.lastname: Kaiser
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: Guy
authors.initials: G
authors.lastname: Cohen
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: Ihab
authors.initials: I
authors.lastname: Abd-Elrahman
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: Galia
authors.initials: G
authors.lastname: Blum
authors.affiliation: Department of Cardiothoracic Surgery, The Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Oz M
authors.initials: OM
authors.lastname: Shapira
authors.affiliation: Department of Cardiothoracic Surgery, The Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Tomer
authors.initials: T
authors.lastname: Koler
authors.affiliation: Institute of Cellular Biology and Pathology N. Simionescu of The Romanian Academy, Bucharest, Romania.
authors.forename: Maya
authors.initials: M
authors.lastname: Simionescu
authors.affiliation: Institute of Cellular Biology and Pathology N. Simionescu of The Romanian Academy, Bucharest, Romania.
authors.forename: Anca V
authors.initials: AV
authors.lastname: Sima
authors.affiliation: Laboratory for Oxidative Stress, Rudjer Boskovic Institute, Zagreb, Croatia.
authors.forename: Neven
authors.initials: N
authors.lastname: Zarkovic
authors.affiliation: Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia.
authors.forename: Kamelija
authors.initials: K
authors.lastname: Zarkovic
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, Milan, Italy.
authors.forename: Marica
authors.initials: M
authors.lastname: Orioli
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Aldini
authors.affiliation: Endocrinology and Metabolism Service, Department of Medicine, The Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Erol
authors.initials: E
authors.lastname: Cerasi
authors.affiliation: Endocrinology and Metabolism Service, Department of Medicine, The Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Gil
authors.initials: G
authors.lastname: Leibowitz
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: Shlomo
authors.initials: S
authors.lastname: Sasson
mesh_terms: D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002417:Cattle; D002460:Cell Line; D016922:Cellular Senescence / Q000187:drug effects*; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005487:Foam Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008954:Models, Biological; D047494:PPAR delta / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology
chemical_list: D000447:Aldehydes; D015415:Biomarkers; D002352:Carrier Proteins; D016166:Free Radical Scavengers; D047494:PPAR delta; C486715:TXNIP protein, human; C027576:4-hydroxy-2-nonenal
keywords: 4-HNE; PPARδ; TXNIP; VEC; atherosclerosis; foam cells; senescence