Osada Makoto, Yatomi Yutaka, Ohmori Tsukasa, Ikeda Hitoshi, Ozaki Yukio
Department of Laboratory Medicine, Yamanashi Medical University, Nakakoma, Yamanashi, Japan.
Biochem Biophys Res Commun. 2002 Dec 6;299(3):483-7. doi: 10.1016/s0006-291x(02)02671-2.
Sphingosine 1-phosphate (Sph-1-P), a bioactive lysophospholipid capable of inducing a wide spectrum of biological responses, acts as an intercellular mediator, through interaction with the endothelial differentiation gene (EDG)/S1P family of G protein-coupled receptors. In this study, the effects of JTE-013, a specific antagonist of the migration-inhibitory receptor EDG-5, on Sph-1-P-elicited responses were examined in human umbilical vein endothelial cells (HUVECs) and vascular smooth muscle cells (SMCs), which expressed EDG-5 protein weakly and abundantly, respectively. This pyrazolopyridine compound reversed the inhibitory effect of Sph-1-P on SMC migration and further enhanced Sph-1-P-stimulated HUVEC migration. In contrast, its effect on Sph-1-P-induced intracellular Ca(2+) mobilization was marginal. Our results indicate that specific regulation of Sph-1-P-modulated migration responses in vascular cells can be achieved by EDG-5 antagonists and that manipulation of Sph-1-P biological activities by each EDG antagonist may lead to a therapeutical application to control vascular diseases.
1-磷酸鞘氨醇（Sph-1-P）是一种能够诱导多种生物学反应的生物活性溶血磷脂，它作为一种细胞间介质，通过与G蛋白偶联受体的内皮分化基因（EDG）/S1P家族相互作用发挥作用。在本研究中，我们在人脐静脉内皮细胞（HUVECs）和血管平滑肌细胞（SMCs）中检测了迁移抑制受体EDG-5的特异性拮抗剂JTE-013对Sph-1-P引发反应的影响，这两种细胞分别弱表达和大量表达EDG-5蛋白。这种吡唑并吡啶化合物逆转了Sph-1-P对平滑肌细胞迁移的抑制作用，并进一步增强了Sph-1-P刺激的人脐静脉内皮细胞迁移。相比之下，它对Sph-1-P诱导的细胞内Ca(2+)动员的影响很小。我们的结果表明，EDG-5拮抗剂可以实现对血管细胞中Sph-1-P调节的迁移反应的特异性调节，并且每种EDG拮抗剂对Sph-1-P生物学活性的操纵可能会导致控制血管疾病的治疗应用。
