The sphingosine kinase 1/sphingosine-1-phosphate pathway in pulmonary arterial hypertension.

TitleThe sphingosine kinase 1/sphingosine-1-phosphate pathway in pulmonary arterial hypertension.
Publication TypeJournal Article
Year of Publication2014
AuthorsChen J, Tang H, Sysol JR, Moreno-Vinasco L, Shioura KM, Chen T, Gorshkova I, Wang L, Huang LShuang, Usatyuk PV, Sammani S, Zhou G, J Raj U, Garcia JGN, Berdyshev E, Yuan JX-J, Natarajan V, Machado RF
JournalAm J Respir Crit Care Med
Volume190
Issue9
Pagination1032-43
Date Published2014 Nov 01
ISSN Number1535-4970
KeywordsAnimals, Humans, Hypertension, Pulmonary, Lysophospholipids, Male, Mice, Phosphotransferases (Alcohol Group Acceptor), Rats, Rats, Sprague-Dawley, Signal Transduction, Sphingosine, Tissue Culture Techniques
Abstract

<p><b>RATIONALE: </b>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.</p><p><b>OBJECTIVES: </b>We aimed to examine whether SphKs and their product, S1P, play a role in the development of pulmonary arterial hypertension (PAH).</p><p><b>METHODS: </b>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.</p><p><b>MEASUREMENTS AND MAIN RESULTS: </b>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.</p><p><b>CONCLUSIONS: </b>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.</p>

DOI10.1164/rccm.201401-0121OC
Alternate JournalAm. J. Respir. Crit. Care Med.
PubMed ID25180446
PubMed Central IDPMC4299585
Grant ListR01 HL111656 / HL / NHLBI NIH HHS / United States
K23 HL098454 / HL / NHLBI NIH HHS / United States
R01 HL115014 / HL / NHLBI NIH HHS / United States
P01HL98050 / HL / NHLBI NIH HHS / United States
R01HL115014 / HL / NHLBI NIH HHS / United States
S10OD010660 / OD / NIH HHS / United States
R01HL111656 / HL / NHLBI NIH HHS / United States
S10 OD010660 / OD / NIH HHS / United States
K23HL098454 / HL / NHLBI NIH HHS / United States
P01 HL098050 / HL / NHLBI NIH HHS / United States
R01 HL066012 / HL / NHLBI NIH HHS / United States
R01HL066012 / HL / NHLBI NIH HHS / United States