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

Xunliang Tong,Yan Wang,Liang Ji,Zhiwei Fu,Jizhao Li,Lemin Zheng,Subramaniam Pennathur,Bing Pan,Pu Lv,Chenguang Niu,Donghui Liu,Anna V Mathew,Yining Huang

doi:10.1186/1475-2840-13-82

Abstract

BackgroundGlycation 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 resultsImmunochemical 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.Conclusion/SignificanceS1P 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.

Highlights

Diabetes mellitus is a systemic metabolic disease and a major risk factor for the development of atherosclerosis [1,2]
Lipid component of diabetic high-density lipoprotein (HDL) improved the up-regulation of COX-2 expression and Prostacyclin I-2 (PGI-2) release in endothelial cells To test whether the glycation modification impaired HDL function in endothelial cells, we used native HDL and non-enzymatically glycated HDL treated with Human umbilical vein endothelial cells (HUVECs) at the final concentration of 30 μg/ml for 6 hours
To eliminate the differences in lipid component, delipidated HDL was used to treat HUVECs and the delipidated apoHDL regulated COX-2 expression slightly more than delipidated diabetic apoHDL. Both apoHDL and diabetic apoHDL partially lost the ability in up-regulating COX-2 expression (Figure 1C), which suggests that such effects are in part mediated by lipid component instead of protein

Summary

Introduction

Diabetes mellitus is a systemic metabolic disease and a major risk factor for the development of atherosclerosis [1,2]. Hyperglycemia causes alterations in lipid metabolism which bring about a series of adverse effects, including enhanced HDL clearance, decreased apoA-1 transcription and accelerated HDL glycation [3,4]. These dramatically altered lipid metabolic changes can promote atherosclerosis [5,6]. 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

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Discussion

Conclusion