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.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Neurology, Peking University First Hospital, Beijing, China.
Xunliang
X
Tong
Hui
H
Peng
Donghui
D
Liu
Liang
L
Ji
Chenguang
C
Niu
Jun
J
Ren
Bing
B
Pan
Jianying
J
Hu
Lemin
L
Zheng
Yining
Y
Huang
D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000201:enzymology; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood*; D008246:Lysophospholipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood; D015854:Up-Regulation / Q000502:physiology
D008075:Lipoproteins, HDL; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D011464:Epoprostenol; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D013110:Sphingosine