Liu Xing, Ren Kun, Suo Rong, Xiong Sheng-Lin, Zhang Qing-Hai, Mo Zhong-Cheng, Tang Zhen-Li, Jiang Yue, Peng Xiao-Shan, Yi Guang-Hui
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.
You Country People's Hospital, Zhuzhou, 412300, Hunan, China.
J Physiol Biochem. 2016 Dec;72(4):657-667. doi: 10.1007/s13105-016-0504-6. Epub 2016 Jul 5.
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).
鞘氨醇-1-磷酸（S1P）已成为参与多种细胞过程调节的关键信号介质，它来源于包括血管内皮细胞在内的多种细胞。S1P积聚在脂蛋白中，尤其是高密度脂蛋白（HDL），并且大多数游离血浆S1P与HDL结合。我们推测与HDL相关的S1P是通过与HDL成熟过程相关的机制释放的。载脂蛋白A-I（ApoA-I）是HDL的主要载脂蛋白，是新生HDL形成和通过ABCA1进行脂质转运的关键因素。此外，ApoA-I能够通过SR-BI促进双向脂质运动。在本研究中，我们证实ApoA-I可以促进人脐静脉内皮细胞（HUVECs）产生和释放S1P。此外，我们证明了ApoA-I诱导的细胞外信号调节激酶1/2（ERK1/2）和鞘氨醇激酶（SphK）激活参与了HUVECs中S1P的释放。抑制剂和小干扰RNA（siRNA）实验表明，ABCA1和SR-BI是ApoA-I诱导的S1P释放和ERK1/2磷酸化所必需的。然而，抑制ABCA1/Janus激酶2（JAK2）或SR-BI/肉瘤病毒癌基因（Src）途径并不能抑制ApoA-I引发的效应。由于ApoA-I激活而释放的S1P可以通过S1P受体（S1PR）1/3刺激（ERK1/2）/SphK1途径。这些结果表明，ApoA-I不仅通过ABCA1和SR-BI促进S1P释放，还通过释放S1P间接激活（ERK1/2）/SphK1途径以触发其受体。总之，我们认为ApoA-I通过ABCA1和SR-BI从内皮细胞诱导释放S1P是一个自我正反馈过程：ApoA-I-（ABCA1和SR-BI）-（S1P释放）-S1PR-ERK1/2-SphK1-（S1P产生）-（ApoA-I诱导更多S1P释放）。
