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The compensatory enrichment of sphingosine -1- phosphate harbored on glycated high-density lipoprotein restores endothelial protective function in type 2 diabetes mellitus

Xunliang Tong1, Pu Lv1, Anna V Mathew3, Donghui Liu4, Chenguang Niu2, Yan Wang4, Liang Ji2, Jizhao Li2, Zhiwei Fu2, Bing Pan2, Subramaniam Pennathur3, Lemin Zheng2* and Yining Huang1*

Author Affiliations

1 Department of Neurology, Peking University First Hospital, Beijing 100034, China

2 The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Peking University Health Science Center, Beijing 100191, China

3 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA

4 Division of cardiology, Zhongshan Hospital affiliated to Xiamen University, Xiamen heart center, Xiamen, Fujian Province 361004, China

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Cardiovascular Diabetology 2014, 13:82  doi:10.1186/1475-2840-13-82

Published: 21 April 2014



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.

Methods and 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.


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.

Sphingosine 1 phosphate; High density lipoprotein; Type 2 diabetes mellitus; Cyclooxygenase-2; Endothelial cells