title: The sphingosine kinase 1/sphingosine-1-phosphate pathway in pulmonary arterial hypertension.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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 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.
authors.affiliation: 1 Section of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine.
authors.forename: Jiwang
authors.initials: J
authors.lastname: Chen
authors.forename: Haiyang
authors.initials: H
authors.lastname: Tang
authors.forename: Justin R
authors.initials: JR
authors.lastname: Sysol
authors.forename: Liliana
authors.initials: L
authors.lastname: Moreno-Vinasco
authors.forename: Krystyna M
authors.initials: KM
authors.lastname: Shioura
authors.forename: Tianji
authors.initials: T
authors.lastname: Chen
authors.forename: Irina
authors.initials: I
authors.lastname: Gorshkova
authors.forename: Lichun
authors.initials: L
authors.lastname: Wang
authors.forename: Long Shuang
authors.initials: LS
authors.lastname: Huang
authors.forename: Peter V
authors.initials: PV
authors.lastname: Usatyuk
authors.forename: Saad
authors.initials: S
authors.lastname: Sammani
authors.forename: Guofei
authors.initials: G
authors.lastname: Zhou
authors.forename: J Usha
authors.initials: JU
authors.lastname: Raj
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
authors.forename: Evgeny
authors.initials: E
authors.lastname: Berdyshev
authors.forename: Jason X-J
authors.initials: JX
authors.lastname: Yuan
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Machado
mesh_terms: D000818:Animals; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology*; D008246:Lysophospholipids / Q000502:physiology*; D008297:Male; D051379:Mice; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000502:physiology; D046509:Tissue Culture Techniques; D000099157:Sphingosine Kinase
chemical_list: D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate
keywords: S1P; S1P receptor 2; pulmonary arterial hypertension; pulmonary vascular remodeling; sphingosine kinase 1