Sphingosine 1-phosphate induces contraction of coronary artery smooth muscle cells via SS1P2
Sphingosine 1-phosphate induces contraction of coronary artery smooth muscle cells via SS1P2
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DOI：
10.1016/s0008-6363(03)00260-8
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发表时间：
2003-04-01
影响因子：
10.8
通讯作者：
Ozaki, Y
中科院分区：
文献类型：
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作者：
Ohmori, T;Yatomi, Y;Ozaki, Y
目的：1-磷酸鞘氨醇（Sph-1-P）是一种来源于活化血小板的生物活性脂质，可能在冠状动脉痉挛中起重要作用，因此在缺血性心脏病的发病机制中起重要作用，因为我们报道了在体内犬心脏模型中，这种溶血磷脂诱导冠状动脉血流量减少[Aprivasc.第46（2000）1191号决议]。在这项研究中，代谢相关的Sph-1-P引起的细胞反应，在人冠状动脉平滑肌细胞（CASMCs）进行了检查。方法与结果：[H-3]鞘氨醇（Sph）掺入CASMCs后，在细胞内转化为[H-3]Sph-1-P，但未观察到刺激依赖性的形成和细胞外释放。此外，发现SIP家族的细胞表面Sph-1-P受体（以前称为EDG）在CASMC中表达。因此，Sph-1-P似乎在CASMC中充当细胞外介质。与Sph-1-P在体内引起的冠状动脉收缩一致，Sph-1-P强烈地引起CASMC收缩，该收缩被新开发的SIP 2（EDG-5）的特异性拮抗剂JTE-013抑制。此外，C3外切酶或Y-27632抑制由Sph-1-P诱导的CASMC收缩，表明Rho参与。最后，外源添加的[3 H]Sph-1-P经历了快速降解。由于脂质磷酸磷酸酶（lipid phosphate phosphatases）是一种能够使Sph-1-P去磷酸化的胞外酶，在CASMC中表达，因此Sph-1-P可能被胞外磷酸酶去磷酸化。结论：来源于血小板并在细胞表面脱磷酸化的Sph-1-P可能通过S1 P（2）/RHO信号通路诱导冠状动脉平滑肌细胞收缩。(C)2003年欧洲心脏病学会。由Elsevier Science B. V.出版，版权所有。
Objectives: Sphingosine 1-phosphate (Sph-1-P), a bioactive lipid derived from activated platelets, may play an important role in coronary artery spasm and hence the pathogenesis of ischemic heart diseases, since we reported that a decrease in coronary blood flow was induced by this lysophospholipid in an in vivo canine heart model [Cardiovasc. Res. 46 (2000) 1191]. In this study, metabolism related to and cellular responses elicited by Sph-1-P were examined in human coronary artery smooth muscle cells (CASMCs). Methods and results: [H-3]Sphingosine (Sph), incorporated into CASMCs, was converted to [H-3]Sph-1-P intracellularly, but its stimulation-dependent formation and extracellular release were not observed. Furthermore, the cell surface Sph-1-P receptors of SIP family (previously called EDG) were found to be expressed in CASMCs. Accordingly, Sph-1-P seems to act as an extracellular mediator in CASMCs. Consistent with Sph-1-P-elicited coronary vasoconstriction in vivo, Sph-1-P strongly induced CASMC contraction, which was inhibited by JTE-013, a newly-developed specific antagonist of SIP2 (EDG-5). Furthermore, C3 exoenzyme or Y-27632 inhibited the CASMC contraction induced by Sph-1-P, indicating Rho involvement. Finally, exogenously-added [3H]Sph-1-P underwent a rapid degradation. Since lipid phosphate phosphatases, ectoenzymes capable of dephosphorylating Sph-1-P, were expressed in CASMCs, Sph-1-P may be dephosphorylated by the ectophosphatases. Conclusions: Sph-1-P, derived from platelets and dephosphorylated on the cell surface, may induce the contraction of coronary artery smooth muscle cells through the S1P(2)/RHO signaling. (C) 2003 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.