Sphingosine-1-Phosphate-Specific G Protein-Coupled Receptors as Novel Therapeutic Targets for Atherosclerosis
Sphingosine-1-Phosphate-Specific G Protein-Coupled Receptors as Novel Therapeutic Targets for Atherosclerosis
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DOI：
10.3390/ph4010117
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发表时间：
2011-01-04
期刊：
影响因子：
4.6
通讯作者：
Takuwa Y
中科院分区：
文献类型：
--
作者：
Okamoto Y;Wang F;Yoshioka K;Takuwa N;Takuwa Y
动脉粥样硬化是一个慢性炎症过程，涉及修饰脂蛋白、单核细胞衍生的巨噬细胞或泡沫细胞、淋巴细胞、内皮细胞（ECs）以及血管平滑肌细胞之间复杂的相互作用。1 - 磷酸鞘氨醇（S1P）是一种具有生物活性的血源性脂质介质，通过5种S1P特异性高亲和力G蛋白偶联受体（S1P1 - S1P5）在多种细胞类型中发挥多效性作用，如细胞增殖、迁移和细胞 - 细胞黏附。其中，S1P1、S1P2和S1P3是主要的受体亚型，在各种组织中广泛表达。现有证据表明，S1P和与高密度脂蛋白结合的S1P通过S1P3以及可能通过S1P1激活Gi信号通路，在内皮细胞（ECs）中发挥抗动脉粥样硬化作用，包括抑制白细胞黏附和刺激内皮型一氧化氮合酶（eNOS），尽管仍存在争议。芬戈莫德（FTY720）的磷酸化产物是除S1P2之外所有S1P受体的高亲和力激动剂，通过下调淋巴细胞上的S1P1发挥免疫抑制剂的作用，它在低密度脂蛋白受体缺失小鼠和载脂蛋白E缺失小鼠中通过抑制淋巴细胞和巨噬细胞功能以及可能刺激内皮细胞功能来抑制动脉粥样硬化，而不影响血浆脂质浓度。与S1P1和S1P3相反，S1P2在载脂蛋白E缺失小鼠中通过激活G12/13 - Rho - Rho激酶（ROCK）促进动脉粥样硬化。S1P2介导单核细胞迁移进入动脉内膜、氧化低密度脂蛋白在单核细胞衍生的巨噬细胞中的积累以及细胞因子的分泌，并且通过抑制Rac、激活NF - κB以及刺激G12/13 - Rho - ROCK下游的3′ - 特异性磷酸肌醇磷酸酶（PTEN），在内皮细胞中抑制eNOS和促进细胞因子分泌。系统性长期给予一种选择性S1P2阻滞剂可显著抑制动脉粥样硬化且无明显毒性。因此，多种S1P受体通过多种机制对动脉粥样硬化进行正向和负向调节。考虑到S1P2在动脉粥样硬化发生中的关键和多方面作用以及S1P2失活对动脉粥样硬化的影响，S1P2是动脉粥样硬化一个特别有前景的治疗靶点。
Atherosclerosis is a chronic inflammatory process involving complex interactions of modified lipoproteins, monocyte-derived macrophages or foam cells, lymphocytes, endothelial cells (ECs), and vascular smooth muscle cells. Sphingosine-1-phosphate (S1P), a biologically active blood-borne lipid mediator, exerts pleiotropic effects such as cell proliferation, migration and cell-cell adhesion in a variety of cell types via five members of S1P-specific high-affinity G protein-coupled receptors (S1P1-S1P5). Among them, S1P1, S1P2 and S1P3 are major receptor subtypes which are widely expressed in various tissues. Available evidence suggest that S1P and HDL-bound S1P exert atheroprotective effects including inhibition of leukocyte adhesion and stimulation of endothelial nitric oxide synthase (eNOS) in endothelial cells (ECs) through the activation of Gi signaling pathway via S1P3 and probably S1P1, although there is still controversy. FTY720, the phosphorylation product of which is a high-affinity agonist for all S1P receptors except S1P2 and act as an immunosuppressant by downregulating S1P1 on lymphocytes, inhibits atherosclerosis in LDL receptor-null mice and apoE-null mice through the inhibition of lymphocyte and macrophage functions and probably stimulation of EC functions, without influencing plasma lipid concentrations. In contrast to S1P1 and S1P3, S1P2 facilitates atherosclerosis by activating G12/13-Rho-Rho kinase (ROCK) in apoE-null mice. S1P2 mediates transmigration of monocytes into the arterial intima, oxidized LDL accumulation and cytokine secretion in monocyte-derived macrophages, and eNOS inhibition and cytokine secretion in ECs through Rac inhibition, NF-κB activation and 3′-specific phosphoinositide phosphatase (PTEN) stimulation downstream of G12/13-Rho-ROCK. Systemic long-term administration of a selective S1P2-blocker remarkably inhibits atherosclerosis without overt toxicity. Thus, multiple S1P receptors positively and negatively regulate atherosclerosis through multitudes of mechanisms. Considering the essential and multi-faceted role of S1P2 in atherogenesis and the impact of S1P2 inactivation on atherosclerosis, S1P2 is a particularly promising therapeutic target for atherosclerosis.