HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation.
HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation.
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DOI：
10.1126/scisignal.aaa2581
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发表时间：
2015-08-11
影响因子：
7.3
通讯作者：
Hla T
中科院分区：
文献类型：
--
作者：
Galvani S;Sanson M;Blaho VA;Swendeman SL;Obinata H;Conger H;Dahlbäck B;Kono M;Proia RL;Smith JD;Hla T
鞘氨醇1-磷酸受体1（S1 P1）在内皮细胞中丰富，在那里它调节血管发育和微血管屏障功能。在研究内皮细胞S1 P1在成年小鼠中的作用时，我们发现内皮细胞S1 P1信号在经历炎症的动脉血管系统区域中增强。在内皮细胞特异性缺失S1 pr 1的小鼠中，促炎性粘附蛋白（如ICAM-1）的丰度增加，而在内皮细胞特异性过表达S1 pr 1的小鼠中，ICAM-1的丰度受到抑制，这表明S1 P1在血管疾病中具有保护功能。分子伴侣ApoM+HDL（HDL）或白蛋白与循环中的1-磷酸鞘氨醇（S1 P）结合;因此，我们在培养的人脐静脉内皮细胞（HUVEC）中检测了与每个分子伴侣结合的S1 P对S1 P1信号传导的影响。HUVECs暴露于ApoM+ HDL-S1 P，而不是白蛋白-S1 P，促进细胞表面S1 P1-β-arrestin 2复合物的形成，减弱促炎细胞因子TNFα激活NF-κB和增加ICAM-1丰度的能力。虽然S1 P结合到任一分子伴侣诱导MAPK活化，但白蛋白-S1 P触发更大的Gi活化和受体内吞作用。高胆固醇血症Apoe−/−小鼠动脉粥样硬化模型中内皮细胞特异性S1 pr 1缺失增强了降主动脉粥样硬化病变的形成。我们提出ApoM+HDL作为S1 P1的偏向性激动剂抑制血管炎症的能力，这可能部分解释HDL的心血管保护功能。
The sphingosine 1-phosphate receptor 1 (S1P1) is abundant in endothelial cells, where it regulates vascular development and microvascular barrier function. In investigating the role of endothelial cell S1P1 in adult mice, we found that the endothelial S1P1 signal was enhanced in regions of the arterial vasculature experiencing inflammation. The abundance of proinflammatory adhesion proteins, such as ICAM-1, was enhanced in mice with endothelial cell–specific deletion of S1pr1 and suppressed in mice with endothelial cell–specific overexpression of S1pr1, suggesting a protective function of S1P1 in vascular disease. The chaperones ApoM+HDL (HDL) or albumin bind to sphingosine 1-phosphate (S1P) in the circulation; therefore, we tested the effects of S1P bound to each chaperone on S1P1 signaling in cultured human umbilical vein endothelial cells (HUVECs). Exposure of HUVECs to ApoM+HDL-S1P, but not to albumin-S1P, promoted the formation of a cell surface S1P1–β-arrestin 2 complex and attenuated the ability of the proinflammatory cytokine TNFα to activate NF-κB and increase ICAM-1 abundance. Although S1P bound to either chaperone induced MAPK activation, albumin-S1P triggered greater Gi activation and receptor endocytosis. Endothelial cell–specific deletion of S1pr1 in the hypercholesterolemic Apoe−/− mouse model of atherosclerosis enhanced atherosclerotic lesion formation in the descending aorta. We propose that the ability of ApoM+HDL to act as a biased agonist on S1P1 inhibits vascular inflammation, which may partially explain the cardiovascular protective functions of HDL.