title: Long term exposure to L-arginine accelerates endothelial cell senescence through arginase-II and S6K1 signaling.
abstract: L-arginine supplementation is proposed to improve health status or as adjunct therapy for diseases including cardiovascular diseases. However, controversial results and even detrimental effects of L-arginine supplementation are reported. We investigate potential mechanisms of L-arginine-induced detrimental effects on vascular endothelial cells. Human endothelial cells were exposed to a physiological (0.1 mmol/L) or pharmacological (0.5 mmol/L) concentration of L-arginine for 30 minutes (acute) or 7 days (chronic). The effects of L-arginine supplementation on endothelial senescence phenotype, i.e., levels of senescence-associated beta-galactosidase, expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, eNOS-uncoupling, arginase-II expression/activity, and mTORC1-S6K1 activity were analyzed. While acute L-arginine treatment enhances endothelial NO production accompanied with superoxide production and activation of S6K1 but no up-regulation of arginase-II, chronic L-arginine supplementation causes endothelial senescence, up-regulation of the adhesion molecule expression, and eNOS-uncoupling (decreased NO and enhanced superoxide production), which are associated with S6K1 activation and up-regulation of arginase-II. Silencing either S6K1 or arginase-II inhibits up-regulation/activation of each other, prevents endothelial dysfunction, adhesion molecule expression, and senescence under the chronic L-arginine supplementation condition. These results demonstrate that S6K1 and arginase-II form a positive circuit mediating the detrimental effects of chronic L-arginine supplementation on endothelial cells.
authors.affiliation: Vascular Biology, Department of Medicine, Division of Physiology, University of Fribourg, CH-1700, Fribourg Switzerland.
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Xiong
authors.forename: Michael Forbiteh
authors.initials: MF
authors.lastname: Fru
authors.forename: Yi
authors.initials: Y
authors.lastname: Yu
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Montani
authors.forename: Xiu-Fen
authors.initials: XF
authors.lastname: Ming
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Yang
mesh_terms: D001119:Arginase / Q000378:metabolism*; D001120:Arginine / Q000633:toxicity*; D015153:Blotting, Western; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects* / Q000502:physiology; D019587:Dietary Supplements / Q000633:toxicity; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001120:Arginine; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D001119:Arginase