title: The compensatory enrichment of sphingosine -1- phosphate harbored on glycated high-density lipoprotein restores endothelial protective function in type 2 diabetes mellitus.
abstract: BACKGROUND
  Glycation of high-density lipoprotein (HDL) decreases its ability to induce cyclooxygenase-2 (COX-2) expression and prostacyclin I-2 (PGI-2) release in endothelial cells. Whether lipid content of HDL, especially sphingosine-1-phosphate (S1P), plays any specific role in restoring the protective function of HDL in type 2 diabetes mellitus (T2DM) is still unknown.
  
  
  RESULTS
  Immunochemical techniques demonstrated that glycated HDL loses its protective function of regulating COX-2 expression compared with diabetic HDL. We proved that the lipid content, especially phospholipid content differed between diabetic HDL and glycated HDL. Levels of HDL-c-bound S1P were increased in T2DM compared with control subjects as detected by UPLC-MS/MS (HDL-c-bound S1P in control subjects vs. T2DM: 309.1 ± 13.71 pmol/mg vs. 382.1 ± 24.45 pmol/mg, P < 0.05). Additionally, mRNA levels of S1P lyase enzymes and S1P phosphatase 1/2 were decreased in peripheral blood by real-time PCR. Antagonist of S1P receptor 1 and 3 (S1PR1/3) diminished the functional difference between apoHDL&PL (HDL containing the protein components and phospholipids) and diabetic apoHDL&PL (diabetic HDL containing the protein components and phospholipids). With different doses of S1P reconstituted on glycated HDL, its function in inducing the COX-2 expression was restored to the same level as diabetic HDL. The mechanism of S1P reconstituted HDL (rHDL) in the process of regulating COX-2 expression involved the phosphorylation of ERK/MAPK-CREB signal pathway.
  
  
  CONCLUSIONS
  S1P harbored on HDL is the main factor which restores its protective function in endothelial cells in T2DM. S1P and its receptors are potential therapeutic targets in ameliorating the vascular dysfunction in T2DM.
authors.forename: Xunliang
authors.initials: X
authors.lastname: Tong
authors.forename: Pu
authors.initials: P
authors.lastname: Lv
authors.forename: Anna V
authors.initials: AV
authors.lastname: Mathew
authors.forename: Donghui
authors.initials: D
authors.lastname: Liu
authors.forename: Chenguang
authors.initials: C
authors.lastname: Niu
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Liang
authors.initials: L
authors.lastname: Ji
authors.forename: Jizhao
authors.initials: J
authors.lastname: Li
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Fu
authors.forename: Bing
authors.initials: B
authors.lastname: Pan
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Pennathur
authors.affiliation: Department of Neurology, Peking University First Hospital, Beijing 100034, China. zhengl@bjmu.edu.cn.
authors.forename: Lemin
authors.initials: L
authors.lastname: Zheng
authors.forename: Yining
authors.initials: Y
authors.lastname: Huang
mesh_terms: D002478:Cells, Cultured; D019610:Cytoprotection / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000473:pathology / Q000517:prevention & control; D006031:Glycosylation; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood*; D008246:Lysophospholipids / Q000097:blood*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood
chemical_list: D008075:Lipoproteins, HDL; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D013110:Sphingosine
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