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

Jiwang Chen, Haiyang Tang, Justin R. Sysol, Liliana Moreno-Vinasco, Krystyna M. Shioura, Tianji Chen, Irina Gorshkova, 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 Machado

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

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 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.

Original languageEnglish (US)
Pages (from-to)1032-1043
Number of pages12
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume190
Issue number9
DOIs
StatePublished - Nov 1 2014
Externally publishedYes

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Pulmonary Hypertension
Lysosphingolipid Receptors
Rodentia
Smooth Muscle Myocytes
Lung
Cell Proliferation
Pulmonary Artery
sphingosine 1-phosphate
sphingosine kinase
Sphingolipids
Hypoxia
Cell Movement
Ligation
Theoretical Models

Keywords

  • Pulmonary arterial hypertension
  • Pulmonary vascular remodeling
  • S1P
  • S1P receptor 2
  • Sphingosine kinase 1

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

The sphingosine kinase 1/sphingosine-1-phosphate pathway in pulmonary arterial hypertension. / Chen, Jiwang; Tang, Haiyang; Sysol, Justin R.; Moreno-Vinasco, Liliana; Shioura, Krystyna M.; Chen, Tianji; Gorshkova, Irina; Wang, Lichun; Huang, Long Shuang; Usatyuk, Peter V.; Sammani, Saad; Zhou, Guofei; Raj, J. Usha; Garcia, Joe G.N.; Berdyshev, Evgeny; Yuan, Jason X.J.; Natarajan, Viswanathan; Machado, Roberto.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 190, No. 9, 01.11.2014, p. 1032-1043.

Research output: Contribution to journalArticle

Chen, J, Tang, H, Sysol, JR, Moreno-Vinasco, L, Shioura, KM, Chen, T, Gorshkova, I, Wang, L, Huang, LS, Usatyuk, PV, Sammani, S, Zhou, G, Raj, JU, Garcia, JGN, Berdyshev, E, Yuan, JXJ, Natarajan, V & Machado, R 2014, 'The sphingosine kinase 1/sphingosine-1-phosphate pathway in pulmonary arterial hypertension', American Journal of Respiratory and Critical Care Medicine, vol. 190, no. 9, pp. 1032-1043. https://doi.org/10.1164/rccm.201401-0121OC
Chen, Jiwang ; Tang, Haiyang ; Sysol, Justin R. ; Moreno-Vinasco, Liliana ; Shioura, Krystyna M. ; Chen, Tianji ; Gorshkova, Irina ; Wang, Lichun ; Huang, Long Shuang ; Usatyuk, Peter V. ; Sammani, Saad ; Zhou, Guofei ; Raj, J. Usha ; Garcia, Joe G.N. ; Berdyshev, Evgeny ; Yuan, Jason X.J. ; Natarajan, Viswanathan ; Machado, Roberto. / The sphingosine kinase 1/sphingosine-1-phosphate pathway in pulmonary arterial hypertension. In: American Journal of Respiratory and Critical Care Medicine. 2014 ; Vol. 190, No. 9. pp. 1032-1043.
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AU - Sysol, Justin R.

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AU - Shioura, Krystyna M.

AU - Chen, Tianji

AU - Gorshkova, Irina

AU - Wang, Lichun

AU - Huang, Long Shuang

AU - Usatyuk, Peter V.

AU - Sammani, Saad

AU - Zhou, Guofei

AU - Raj, J. Usha

AU - Garcia, Joe G.N.

AU - Berdyshev, Evgeny

AU - Yuan, Jason X.J.

AU - Natarajan, Viswanathan

AU - Machado, Roberto

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N2 - 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 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.

AB - 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 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.

KW - Pulmonary arterial hypertension

KW - Pulmonary vascular remodeling

KW - S1P

KW - S1P receptor 2

KW - Sphingosine kinase 1

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