title: X-linked inhibitor of apoptosis protein is an important regulator of vascular endothelial growth factor-dependent bovine aortic endothelial cell survival.
abstract: Vascular endothelial growth factor (VEGF) is a critical regulator of endothelial cell biology and vascular function. Chronic VEGF treatment has been shown to inhibit tumor necrosis factor-induced apoptosis in endothelial cells. However, the mechanism for this cell survival is unclear. Interestingly, VEGF also enhances the expression of X-linked inhibitor of apoptosis (XIAP), a well-established antiapoptotic factor. XIAP has been shown to suppress apoptosis by blocking caspase activity in cancer cells, but it remains under studied in the endothelium. Therefore, we hypothesized that VEGF affects important endothelial functions, such as apoptosis and cell migration, by regulating XIAP expression and downstream caspase activity. To test this hypothesis, caspase activity, apoptosis, and cell migration were assessed following XIAP overexpression or depletion in bovine aortic endothelial cells. Much like VEGF treatment, ectopic expression of XIAP blocked tumor necrosis factor-induced apoptosis. Surprisingly, the mechanism was caspase-independent. In addition, XIAP-associated cell survival was the result of enhanced nitric oxide (NO) production, and XIAP was partially localized in caveolae. In these lipid rafts, XIAP interacted with a regulator of NO production, caveolin-1, via a binding motif (FtFgtwiY, where the bold letters represent aromatic amino acids) in the baculoviral IAP repeat-3 domain. Endothelial NO synthase binding to caveolin-1 was competitively inhibited by XIAP, suggesting that XIAP acts as a modulator of NO production by releasing endothelial NO synthase from caveolin-1. Further studies showed that endothelial cell migration was also controlled by XIAP-dependent NO. Taken together, these results suggest that XIAP plays a novel role in endothelial cells, interacting with caveolin-1 and acting as a regulator of vascular antiatherogenic function.
authors.affiliation: Department of Molecular Biology & Institute of Nanosensor and Biotechnology, BK21 Graduate Program for RNA Biology, Dankook University, San 44-1, Jookjeon-dong, Suji-ku, Yongin-si, Gyeonggi-do, 448-701, Korea.
authors.forename: Jongmin
authors.initials: J
authors.lastname: Kim
authors.forename: Jongbong
authors.initials: J
authors.lastname: Park
authors.forename: Seungmin
authors.initials: S
authors.lastname: Choi
authors.forename: Sung-Gil
authors.initials: SG
authors.lastname: Chi
authors.forename: Amy L
authors.initials: AL
authors.lastname: Mowbray
authors.forename: Hanjoong
authors.initials: H
authors.lastname: Jo
authors.forename: Heonyong
authors.initials: H
authors.lastname: Park
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002417:Cattle; D051242:Caveolin 1 / Q000378:metabolism*; D002465:Cell Movement; D002470:Cell Survival; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology*; D009569:Nitric Oxide / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000502:physiology*
chemical_list: D051242:Caveolin 1; D042461:Vascular Endothelial Growth Factor A; D051636:X-Linked Inhibitor of Apoptosis Protein; D009569:Nitric Oxide; D020169:Caspases