ApoA-I/SR-BI modulates S1P/S1PR2-mediated inflammation through the PI3K/Akt signaling pathway in HUVECs.
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.
Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, 28 W Changsheng Road, Hengyang, Hunan, 421001, China.
Kun
K
Ren
Department of Pathology, Maternal and Child Health Hospital of Hubei Province, Wuhan City, Hubei Province, 430072, China.
Yan-Ju
YJ
Lu
Department of Histology and Embryology, University of South China, Hengyang, Hunan, 421001, China.
Zhong-Cheng
ZC
Mo
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
X
-Liu
Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, 28 W Changsheng Road, Hengyang, Hunan, 421001, China.
Zhen-Li
ZL
Tang
Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, 28 W Changsheng Road, Hengyang, Hunan, 421001, China.
Yue
Y
Jiang
Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, 28 W Changsheng Road, Hengyang, Hunan, 421001, China.
Xiao-Shan
XS
Peng
Department of Pathology, Maternal and Child Health Hospital of Hubei Province, Wuhan City, Hubei Province, 430072, China.
Li
L
Li
Clinical Research Institution, The First Affiliated Hospital, University of South China, Hengyang, Hunan, 421001, China.
Qing-Hai
QH
Zhang
Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, 28 W Changsheng Road, Hengyang, Hunan, 421001, China. ghyi6108@163.com.
Guang-Hui
GH
Yi
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003517:Cyclopentanes / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000819:agonists / Q000378:metabolism; D053583:Interleukin-1beta / Q000819:agonists / Q000378:metabolism; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000819:agonists / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D013882:Thiosemicarbazones / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000819:agonists / Q000378:metabolism
C526651:2-hexyl-1-cyclopentanone thiosemicarbazone; C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D003517:Cyclopentanes; C508609:IL10 protein, human; C508585:IL1B protein, human; D053583:Interleukin-1beta; D008077:Lipoproteins, LDL; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; D011994:Recombinant Proteins; C477522:S1PR2 protein, human; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D000081025:Sphingosine-1-Phosphate Receptors; C439524:TNF protein, human; D013882:Thiosemicarbazones; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; D016753:Interleukin-10; C060506:sphingosine 1-phosphate; D058539:Phosphatidylinositol 3-Kinase; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D013110:Sphingosine
HDL; Inflammation; S1P/S1PR2; apoA-I/SR-BI