The Sphingosine Kinase 1/Sphingosine-1-Phosphate Pathway in Pulmonary Arterial Hypertension
The Sphingosine Kinase 1/Sphingosine-1-Phosphate Pathway in Pulmonary Arterial Hypertension
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DOI：
10.1164/rccm.201401-0121oc
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发表时间：
2014-11-01
影响因子：
24.7
通讯作者：
Machado, Roberto F.
中科院分区：
文献类型：
--
作者：
Chen, Jiwang;Tang, Haiyang;Machado, Roberto F.
基本原理：鞘氨醇激酶（SphKs）1和2调节生物活性鞘脂鞘氨醇-1-磷酸（S1 P）的合成，S1 P是促进细胞增殖、迁移和血管生成的重要脂质介质。目的：我们旨在研究SphKs及其产物S1 P是否在肺动脉高压（PAH）的发展中发挥作用。将SphK 1（- /-）、SphK 2（-/-）和S1 P裂解酶杂合（Sgpl 1（+/-））小鼠、药理学SphK抑制剂（SKI 2）和S1 P受体2（S1 PR 2）拮抗剂（JTE 013）用于缺氧介导的肺动脉高压（HPH）的啮齿动物模型。测量和主要结果：SphK 1的mRNA和蛋白水平，但不是SphK 2，肺组织中的S1 P水平从PAH患者和肺动脉平滑肌细胞（PASMCs）从PAH患者，并在肺HPH的实验啮齿类动物模型测量和主要结果：SphK 1的mRNA和蛋白水平显着增加。在PAH患者和来自HPH啮齿动物模型的PA患者的肺中，S1 P水平升高。与SphK 2（-/-）小鼠不同，SphK 1（-/-）小鼠对HPH有保护作用，而Sgpl 1（+/-）小鼠对HPH更敏感。药理学SphK 1和S1 PR 2抑制可防止啮齿动物HPH模型中HPH的发展。SphK 1的过表达和S1 P的刺激可能通过连接S1 PR 2促进PASMC增殖在体外，而SphK 1缺陷抑制PASMC proliferation.Conclusions：SphK 1/S1 P轴是一个新的途径，在PAH，促进PASMC增殖，肺血管重构的主要贡献者。我们的研究结果表明，这一途径是一个潜在的治疗PAH的目标。
Rationale: Sphingosine kinases (SphKs) 1 and 2 regulate the synthesis of the bioactive sphingolipid sphingosine-1-phosphate (S1P), an important lipid mediator that promotes cell proliferation, migration, and angiogenesis.Objectives: We aimed to examine whether SphKs and their product, S1P, play a role in the development of pulmonary arterial hypertension (PAH).Methods: SphK1(- /-), SphK2(-/-), and S1P lyase heterozygous (Sgpl1(+/-)) mice, a pharmacologic SphK inhibitor (SKI2), and a S1P receptor 2 (S1PR2) antagonist (JTE013) were used in rodent models of hypoxia-mediated pulmonary hypertension (HPH). S1P levels in lung tissues from patients with PAH and pulmonary arteries (PAs) from rodent models of HPH were measured.Measurements and Main Results: rnRNA and protein levels of SphK1, but not SphK2, were significantly increased in the lungs and isolated PA smooth muscle cells (PASMCs) from patients with PAH, and in lungs of experimental rodent models of HPH. S1P levels were increased in lungs of patients with PAH and PAs from rodent models of HPH. Unlike SphK2(-/-) mice, SphK1(-/-) mice were protected against HPH, whereas Sgpl1(+/-) mice were more susceptible to HPH. Pharmacologic SphK1 and S1PR2 inhibition prevented the development of HPH in rodent models of HPH. Overexpression of SphK1 and stimulation with S1P potentially via ligation ofS1PR2 promoted PASMC proliferation in vitro, whereas SphK1 deficiency inhibited PASMC proliferation.Conclusions: The SphK1/S1P axis is a novel pathway in PAH that promotes PASMC proliferation, a major contributor to pulmonary vascular remodeling. Our results suggest that this pathway is a potential therapeutic target in PAH.