The Sphingosine Kinase 1/Sphingosine-1-Phosphate Pathway in Pulmonary Arterial Hypertension

作者：Jiwang Chen, Haiyang Tang, Justin R. Sysol, Liliana Moreno‐Vinasco, Krystyna M. Shioura, Tianji Chen, И. А. Горшкова, Lichun Wang, Long Shuang Huang, Peter V. Usatyuk, Saad Sammani, Guofei Zhou, J. Usha Raj, Joe G. N. Garcia, Evgeny Berdyshev, Jason X.‐J. Yuan, Viswanathan Natarajan, Roberto F. Machado · 发表于：American Journal of Respiratory and Critical Care Medicine · 年份：2014 · DOI：10.1164/rccm.201401-0121oc · 被引用次数：147 · 研究领域：Sphingolipid Metabolism and Signaling、Pulmonary Hypertension Research and Treatments、Protease and Inhibitor Mechanisms

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: mRNA 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 of S1PR2 promoted PASMC proliferation in vitro, whereas SphK1 deficiency inhibited PASMC proliferation. CONCLUSIONS: The SphK1/S1P axis is a no...