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ApoA-I/SR-BI modulates S1P/S1PR2-mediated inflammation through the PI3K/Akt signaling pathway in HUVECs

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Abstract

Endothelial dysfunction plays a vital role during the initial stage of atherosclerosis. Oxidized low-density lipoprotein (ox-LDL) induces vascular endothelial injury and vessel wall inflammation. Sphingosine-1-phosphate (S1P) exerts numerous vasoprotective effects by binding to diverse S1P receptors (S1PRs; S1PR1-5). A number of studies have shown that in endothelial cells (ECs), S1PR2 acts as a pro-atherosclerotic mediator by stimulating vessel wall inflammation through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Scavenger receptor class B member I (SR-BI), a high-affinity receptor for apolipoprotein A-I (apoA-I)/high-density lipoprotein (HDL), inhibits nuclear factor-κB (NF-κB) translocation and decreases the plasma levels of inflammatory mediators via the PI3K/Akt pathway. We hypothesized that the inflammatory effects of S1P/S1PR2 on ECs may be regulated by apoA-I/SR-BI. The results showed that ox-LDL, a pro-inflammatory factor, augmented the S1PR2 level in human umbilical vein endothelial cells (HUVECs) in a dose- and time-dependent manner. In addition, S1P/S1PR2 signaling influenced the levels of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-10, aggravating inflammation in HUVECs. Moreover, the pro-inflammatory effects induced by S1P/S1PR2 were attenuated by SR-BI overexpression and enhanced by an SR-BI inhibitor, BLT-1. Further experiments showed that the PI3K/Akt signaling pathway was involved in this process. Taken together, these results demonstrate that apoA-I/SR-BI negatively regulates S1P/S1PR2-mediated inflammation in HUVECs by activating the PI3K/Akt signaling pathway.

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Abbreviations

ox-LDL:

Oxidized low-density lipoprotein

S1P:

Sphingosine-1-phosphate

HDL:

High-density lipoprotein

S1PR:

S1P receptor

ECs:

Endothelial cells

PI3K:

Phosphatidylinositol 3-kinase

SR-BI:

Scavenger receptor class B member 1

Apo:

Apolipoprotein

NF-κB:

Nuclear factor-κB

HUVECs:

Human umbilical vein endothelial cells

TNF:

Tumor necrosis factor

IL:

Interleukin

RCT:

Reverse cholesterol transport

GPCR:

G-protein coupled receptor

VSMC:

Vascular smooth muscle cell

apoE−/−:

apoE deficient

S1PR2−/−:

S1PR2 deficient

S1PR2+/+:

S1PR2 non-deficient

IFN:

Interferon

MCP-1:

Monocyte chemotactic protein-1

VCAM-1:

Vascular cell adhesion molecule 1

ICAM-1:

Intercellular cell adhesion molecule-1

HDL-C:

HDL-cholesterol

HCAECs:

Human coronary artery endothelial cells

NO:

Nitric oxide

eNOS:

Endothelial nitric oxide synthase

PMN:

Polymorphonuclear neutrophil

MSCs:

Mesenchymal stem cells

DMEM:

Dulbecco’s Modified Eagle’s Medium

FBS:

Fetal bovine serum

p-PI3K:

Phosphorylated PI3K

p-Akt:

Phosphorylated Akt

ATCC:

American Type Culture Collection

PBS:

Phosphate-buffered saline

BSA:

Bovine serum albumin

HPLC:

High-performance liquid chromatography

alb-S1P:

Albumin-bound S1P

PMSF:

Phenylmethylsulfonyl fluoride

PVDF:

Polyvinylidene difluoride

ECL:

Enhanced chemiluminescence

RT-PCR:

Real-time quantitative polymerase chain reaction

ELISA:

Enzyme-linked immunosorbent assay

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Acknowledgements

This work was sponsored by the National Natural Science Foundation of China (Nos. 81270360 and 81670401), the Scientific Research Fund of the Hunan Provincial Education Department (13C838), the Science and Technology Planning Project of the Hunan Provincial Science and Technology Department (2014FJ2012), the Aid Program for Science and Technology Innovative Research Team in Higher Educational Institutions of Hunan Province (2008-244), and the construct program of the key discipline in Hunan Province (2011-76).

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Authors and Affiliations

  1. Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, 28 W Changsheng Road, Hengyang, Hunan, 421001, China

    Kun Ren, Zhen-Li Tang, Yue Jiang, Xiao-Shan Peng & Guang-Hui Yi

  2. Department of Pathology, Maternal and Child Health Hospital of Hubei Province, Wuhan City, Hubei Province, 430072, China

    Yan-Ju Lu & Li Li

  3. Department of Histology and Embryology, University of South China, Hengyang, Hunan, 421001, China

    Zhong-Cheng Mo

  4. National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China

    Xing -Liu

  5. Clinical Research Institution, The First Affiliated Hospital, University of South China, Hengyang, Hunan, 421001, China

    Qing-Hai Zhang

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  1. Kun Ren
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  2. Yan-Ju Lu
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Correspondence to Guang-Hui Yi.

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Kun Ren and Yan-Ju Lu contributed equally to this work.

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Ren, K., Lu, YJ., Mo, ZC. et al. ApoA-I/SR-BI modulates S1P/S1PR2-mediated inflammation through the PI3K/Akt signaling pathway in HUVECs. J Physiol Biochem 73, 287–296 (2017). https://doi.org/10.1007/s13105-017-0553-5

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