title: Insulin-like growth factor-1 regulates glutathione peroxidase expression and activity in vascular endothelial cells: Implications for atheroprotective actions of insulin-like growth factor-1.
abstract: Oxidative stress promotes endothelial cell senescence and endothelial dysfunction, important early steps in atherogenesis. To investigate potential antioxidant effects of IGF-1 we treated human aortic endothelial cells (hAECs) with 0-100ng/mL IGF-1 prior to exposure to native or oxidized low-density lipoprotein (oxLDL). IGF-1 dose- and time- dependently reduced basal- and oxLDL-induced ROS generation. IGF-1 did not alter superoxide dismutase or catalase activity but markedly increased activity of glutathione peroxidase (GPX), a crucial antioxidant enzyme, via a phosphoinositide-3 kinase dependent pathway. IGF-1 did not increase GPX1 mRNA levels but increased GPX1 protein levels by 2.6-fold at 24h, and altered selenocysteine-incorporation complex formation on GPX1 mRNA. Furthermore, IGF-1 blocked hydrogen peroxide induced premature cell senescence in hAECs. In conclusion, IGF-1 upregulates GPX1 expression in hAECs via a translational mechanism, which may play an important role in the ability of IGF-1 to reduce endothelial cell oxidative stress and premature senescence. Our findings have major implications for understanding vasculoprotective effects of IGF-1.
authors.affiliation: Tulane University School of Medicine, New Orleans, LA 70112, USA. yhigashi@tulane.edu
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Higashi
authors.forename: Arvind
authors.initials: A
authors.lastname: Pandey
authors.forename: Brett
authors.initials: B
authors.lastname: Goodwin
authors.forename: Patrice
authors.initials: P
authors.lastname: Delafontaine
mesh_terms: D001011:Aorta / Q000166:cytology; D001161:Arteriosclerosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D015153:Blotting, Western; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017279:Selenocysteine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D000094765:Glutathione Peroxidase GPX1
chemical_list: D008077:Lipoproteins, LDL; D016877:Oxidants; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C099252:oxidized low density lipoprotein; D017279:Selenocysteine; D007334:Insulin-Like Growth Factor I; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D019869:Phosphatidylinositol 3-Kinases; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human