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.
Keywords:
HDL; Inflammation; S1P/S1PR2; apoA-I/SR-BI.
MeSH terms
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Active Transport, Cell Nucleus / drug effects
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Apolipoprotein A-I / genetics
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Apolipoprotein A-I / metabolism*
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Cells, Cultured
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Cyclopentanes / pharmacology
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / immunology
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Endothelium, Vascular / metabolism*
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Gene Expression Regulation / drug effects
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Human Umbilical Vein Endothelial Cells / cytology
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / immunology
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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Interleukin-10 / agonists
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Interleukin-10 / metabolism
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Interleukin-1beta / agonists
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Interleukin-1beta / metabolism
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Kinetics
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Lipoproteins, LDL / adverse effects
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Lipoproteins, LDL / genetics
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Lipoproteins, LDL / metabolism
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Lysophospholipids / metabolism*
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Phosphatidylinositol 3-Kinase / metabolism*
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Proto-Oncogene Proteins c-akt / agonists
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Proto-Oncogene Proteins c-akt / metabolism
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Receptors, Lysosphingolipid / agonists*
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Receptors, Lysosphingolipid / genetics
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Receptors, Lysosphingolipid / metabolism
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Scavenger Receptors, Class B / agonists*
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Scavenger Receptors, Class B / antagonists & inhibitors
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Scavenger Receptors, Class B / genetics
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Scavenger Receptors, Class B / metabolism
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Signal Transduction* / drug effects
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Sphingosine / analogs & derivatives*
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Sphingosine / metabolism
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Sphingosine-1-Phosphate Receptors
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Thiosemicarbazones / pharmacology
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Tumor Necrosis Factor-alpha / agonists
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Tumor Necrosis Factor-alpha / metabolism
Substances
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2-hexyl-1-cyclopentanone thiosemicarbazone
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APOA1 protein, human
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Apolipoprotein A-I
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Cyclopentanes
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IL10 protein, human
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IL1B protein, human
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Interleukin-1beta
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Lipoproteins, LDL
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Lysophospholipids
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Receptors, Lysosphingolipid
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Recombinant Proteins
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S1PR2 protein, human
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SCARB1 protein, human
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Scavenger Receptors, Class B
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Sphingosine-1-Phosphate Receptors
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TNF protein, human
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Thiosemicarbazones
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Tumor Necrosis Factor-alpha
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oxidized low density lipoprotein
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Interleukin-10
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sphingosine 1-phosphate
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Phosphatidylinositol 3-Kinase
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AKT1 protein, human
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Proto-Oncogene Proteins c-akt
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Sphingosine