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High-density lipoprotein of patients with Type 2 Diabetes Mellitus upregulates cyclooxgenase-2 expression and prostacyclin I-2 release in endothelial cells: relationship with HDL-associated sphingosine-1-phosphate

Xunliang Tong1, Hui Peng3, Donghui Liu2, Liang Ji2, Chenguang Niu2, Jun Ren4, Bing Pan2, Jianying Hu3, 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 College of Urban and Environmental Sciences, Peking University, Beijing 100871, China

4 Division of Kinesiology and Health & Biomedical Science PhD Program, University of Wyoming College of Health Sciences, Laramie, WY, USA

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Cardiovascular Diabetology 2013, 12:27  doi:10.1186/1475-2840-12-27

Published: 30 January 2013



Dysfunctional high-density lipoprotein (HDL) may have pro-inflammatory effects on the endothelial cells,which causes atherosclerosis in type 2 diabetes mellitus (T2DM). HDL is a major carrier of sphingosine-1-phosphate (S1P) in plasma while S1P exhibits multiple biological activities. However, potential role of HDL and S1P in T2DM remains unexplored. We hypothesized that diabetic HDL with higher contents of S1P exerts beneficial effects on the vascular system.


Subjects with T2DM with or without proved large arteries atherosclerosis and normal controls (n=15 for each group) were recruited in the present study. HDL was isolated from the subjects by ultracentrifugation. The levels of HDL-associated S1P were determined by UPLC-MS/MS. The protective function of diabetic HDL and S1P was evaluated by measuring cyclooxygenase-2 (COX-2) expression and prostacyclin I-2 (PGI-2) release by human umbilical vein endothelial cells (HUVECs) using western blot and enzyme-linked immunosorbent assay (ELISA), respectively.


The S1P levels in isolated HDL were significantly increased in T2DM subjects compared with controls (235.6 ± 13.4 vs 195.0 ± 6.4 ng/mg, P< 0.05). The diabetic HDL exerted greater protective effects on inducing COX-2 expression and PGI-2 release by HUVECs than those of control HDL (p < 0.05, p < 0.01, respectively). Pertussis toxin, a common inhibitor of G-couple protein receptors, and VPC 23019, an antagonist of S1P receptor 1 and 3 significantly attenuated HDL-induced COX-2 expression and PGI-2 release.


Diabetic HDL carries higher level of S1P compared with normal HDL, which has the potential to contribute to protective effects on endothelial cells by inducing COX-2 expression and PGI-2 release. These findings provide a new insight of S1P function in T2DM patients, possibly leading to a new therapeutic target.

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