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ApoA-I induces S1P release from endothelial cells through ABCA1 and SR-BI in a positive feedback manner

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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).

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Abbreviations

ABC:

ATP-binding cassette

ERK1/2:

Extracellular receptor kinase 1/2

FC:

Free cholesterol

HDAC:

Histone deacetylases

HDL:

High-density lipoprotein

HDL-S1P:

HDL-associated S1P

HPLC:

High-performance liquid chromatography

HUVECs:

Human umbilical vein endothelial cells

JAK2:

Janus kinase 2

PL:

Phospholipid

S1P:

Sphingosine-1-phosphate

S1PR:

S1P receptor

SphK:

Sphingosine kinase

SR-BI:

Scavenger receptor class B type I

TRAF2:

TNF receptor-associated factor 2

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Acknowledgments

This work was sponsored by the National Natural Science Foundation of China (Nos. 81270360 and 31400652), Scientific Research Fund of Hunan Provincial Education Department (13C838), the Science and Technology Planning Project of Hunan Provincial Science and Technology Department (2014FJ2012), the Aid Program for Science and Technology Innovative Research Team in Higher Educational Institutions (2008-244) of Hunan Province, and the construct program of the key discipline in Hunan Province, China (Basic Medicine Sciences in University of South China, Xiangjiaofa No. [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 City, 421001, Hunan Province, China

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

    2. You Country People’s Hospital, Zhuzhou, 412300, Hunan, China

      Sheng-Lin Xiong

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

      Qing-Hai Zhang

    4. Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, Hunan, 421001, China

      Zhong-Cheng Mo

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    1. Xing Liu
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    Correspondence to Guang-Hui Yi.

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    Xing Liu and Kun Ren contributed equally to this work.

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    Liu, X., Ren, K., Suo, R. et al. ApoA-I induces S1P release from endothelial cells through ABCA1 and SR-BI in a positive feedback manner. J Physiol Biochem 72, 657–667 (2016). https://doi.org/10.1007/s13105-016-0504-6

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    • DOI: https://doi.org/10.1007/s13105-016-0504-6

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