title: SIRT1 mediates Sphk1/S1P-induced proliferation and migration of endothelial cells.
abstract: Angiogenesis is one of the most important components of embryonic organ formation and vessel growth after birth. Sphingosine kinase 1 (Sphk1) and S1P has been confirmed to participate in various cell signaling pathways and physiological processes including neovascularisation. However, the mechanisms that Sphk1/S1P regulates neovascularisation remain unclear. In this study, we elucidated that Sphk1/S1P upregulates sirtuin 1 (SIRT1), a NAD+ dependent deacetylases protease which exerts multiple cellular functions, to regulate the proliferation and migration of endothelial cells. By using CCK8 and Transwell assays, we demonstrated that Sphk1 and SIRT1 knockdown could significantly decrease proliferation and migration of HUVEC cells. Sphk1 inhibition results in SIRT1 downregulation which could be reversed by exogenous S1P in HUVEC cells. Treatment of HUVECs with S1P reverses the impaired proliferation and migration caused by SIRT1 knockdown. Furthermore, Sphk1 knockdown inhibits the phosphorylation of P38 MAPK, ERK and AKT. Treatment of HUVECs with PD98059, SB203580 and Wortmannin, which are the inhibitors of ERK, P38 MAPK and AKT respectively, resulted in decreased SIRT1 expression and reduced migration of HUVEC cells. Thus, we conclude that Sphk1/S1P induces SIRT1 upregulation through multiple pathways including P38 MAPK, ERK and AKT signals. This is the first report to disclose the existence and roles of Sphk1/S1P/SIRT1 axis in regulation of endothelial cell proliferation and migration, which may provide a theoretical basis for angiogenesis.
authors.affiliation: Department of Clinical Laboratory, Lanzhou Military Command General Hospital of the People's Liberation Army, Lanzhou 730050, Gansu, PR China; Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China.
authors.forename: Feng-Jun
authors.initials: FJ
authors.lastname: Xiao
authors.affiliation: Qinghai Provincial People's Hospital, Xining 810007, Qinghai, PR China.
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Shi
authors.affiliation: Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China.
authors.forename: Yi-Kun
authors.initials: YK
authors.lastname: Zhang
authors.affiliation: Qinghai Provincial People's Hospital, Xining 810007, Qinghai, PR China.
authors.forename: Qin Qin
authors.initials: QQ
authors.lastname: Xu
authors.affiliation: Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Zhang
authors.affiliation: Department of Clinical Laboratory, Lanzhou Military Command General Hospital of the People's Liberation Army, Lanzhou 730050, Gansu, PR China. Electronic address: haxq@yahoo.com.
authors.forename: Xiao-Qin
authors.initials: XQ
authors.lastname: Ha
authors.affiliation: Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China. Electronic address: wangls@bmi.ac.cn.
authors.forename: Li-Sheng
authors.initials: LS
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D060888:Real-Time Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004791:Enzyme Inhibitors; C466999:SPHKAP protein, human; D056564:Sirtuin 1
keywords: HUVEC; Migration; Proliferation; S1P; SIRT1; Sphk1