title: ApoA-I induces S1P release from endothelial cells through ABCA1 and SR-BI in a positive feedback manner.
abstract: Sphingosine-1-phosphate (S1P), which has emerged as a pivotal signaling mediator that participates in the regulation of multiple cellular processes, is derived from various cells, including vascular endothelial cells. S1P accumulates in lipoproteins, especially HDL, and the majority of free plasma S1P is bound to HDL. We hypothesized that HDL-associated S1P is released through mechanisms associated with the HDL maturation process. ApoA-I, a major HDL apolipoprotein, is a critical factor for nascent HDL formation and lipid trafficking via ABCA1. Moreover, apoA-I is capable of promoting bidirectional lipid movement through SR-BI. In the present study, we confirmed that apoA-I can facilitate the production and release of S1P by HUVECs. Furthermore, we demonstrated that ERK1/2 and SphK activation induced by apoA-I is involved in the release of S1P from HUVECs. Inhibitor and siRNA experiments showed that ABCA1 and SR-BI are required for S1P release and ERK1/2 phosphorylation induced by apoA-I. However, the effects triggered by apoA-I were not suppressed by inhibiting ABCA1/JAK2 or the SR-BI/Src pathway. S1P released due to apoA-I activation can stimulate the (ERK1/2)/SphK1 pathway through S1PR (S1P receptor) 1/3. These results indicated that apoA-I not only promotes S1P release through ABCA1 and SR-BI but also indirectly activates the (ERK1/2)/SphK1 pathway by releasing S1P to trigger their receptors. In conclusion, we suggest that release of S1P induced by apoA-I from endothelial cells through ABCA1 and SR-BI is a self-positive-feedback process: apoA-I-(ABCA1 and SR-BI)-(S1P release)-S1PR-ERK1/2-SphK1-(S1P production)-(more S1P release induced by apoA-I).
authors.affiliation: Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, 28 W Changsheng Road, Hengyang City, 421001, Hunan Province, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, 28 W Changsheng Road, Hengyang City, 421001, Hunan Province, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Ren
authors.affiliation: Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, 28 W Changsheng Road, Hengyang City, 421001, Hunan Province, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Suo
authors.affiliation: You Country People's Hospital, Zhuzhou, 412300, Hunan, China.
authors.forename: Sheng-Lin
authors.initials: SL
authors.lastname: Xiong
authors.affiliation: Clinical Research Institution, The First Affiliated Hospital, University of South China, Hengyang, Hunan, 421001, China.
authors.forename: Qing-Hai
authors.initials: QH
authors.lastname: Zhang
authors.affiliation: Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, Hunan, 421001, China.
authors.forename: Zhong-Cheng
authors.initials: ZC
authors.lastname: Mo
authors.affiliation: Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, 28 W Changsheng Road, Hengyang City, 421001, Hunan Province, China.
authors.forename: Zhen-Li
authors.initials: ZL
authors.lastname: Tang
authors.affiliation: Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, 28 W Changsheng Road, Hengyang City, 421001, Hunan Province, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, 28 W Changsheng Road, Hengyang City, 421001, Hunan Province, China.
authors.forename: Xiao-Shan
authors.initials: XS
authors.lastname: Peng
authors.affiliation: Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, 28 W Changsheng Road, Hengyang City, 421001, Hunan Province, China. ghyi6108@163.com.
authors.forename: Guang-Hui
authors.initials: GH
authors.lastname: Yi
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D016632:Apolipoprotein A-I / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: C577836:ABCA1 protein, human; C505693:APOA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D048868:Adaptor Proteins, Signal Transducing; D016632:Apolipoprotein A-I; D008246:Lysophospholipids; D034741:RNA, Small Interfering; C495124:SCARB1 protein, human; C466999:SPHKAP protein, human; D051122:Scavenger Receptors, Class B; C060506:sphingosine 1-phosphate; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D013110:Sphingosine
keywords: ABCA1; Release; S1P; S1P receptors; SR-BI; SphK