Journal article
Sphingosine‐1‐Phosphate is Involved in the Occlusive Arteriopathy of Pulmonary Arterial Hypertension
Pulmonary circulation, Vol.6(3), pp.369-380
09/2016
DOI: 10.1086/687766
PMCID: PMC5019090
PMID: 27683614
Abstract
Despite several advances in the pathobiology of pulmonary arterial hypertension (PAH), its pathogenesis is not completely understood. Current therapy improves symptoms but has disappointing effects on survival. Sphingosine‐1‐phosphate (S1P) is a lysophospholipid synthesized by sphingosine kinase 1 (SphK1) and SphK2. Considering the regulatory roles of S1P in several tissues leading to vasoconstriction, inflammation, proliferation, and fibrosis, we investigated whether S1P plays a role in the pathogenesis of PAH. To test this hypothesis, we used plasma samples and lung tissue from patients with idiopathic PAH (IPAH) and the Sugen5416/hypoxia/normoxia rat model of occlusive PAH. Our study revealed an increase in the plasma concentration of S1P in patients with IPAH and in early and late stages of PAH in rats. We observed increased expression of both SphK1 and SphK2 in the remodeled pulmonary arteries of patients with IPAH and PAH rats. Exogenous S1P stimulated the proliferation of cultured rat pulmonary arterial endothelial and smooth‐muscle cells. We also found that 3 weeks of treatment of late‐stage PAH rats with an SphK1 inhibitor reduced the increased plasma levels of S1P and the occlusive pulmonary arteriopathy. Although inhibition of SphK1 improved cardiac index and the total pulmonary artery resistance index, it did not reduce right ventricular systolic pressure or right ventricular hypertrophy. Our study supports that S1P is involved in the pathogenesis of occlusive arteriopathy in PAH and provides further evidence that S1P signaling may be a novel therapeutic target.
Details
- Title: Subtitle
- Sphingosine‐1‐Phosphate is Involved in the Occlusive Arteriopathy of Pulmonary Arterial Hypertension
- Creators
- Salina Gairhe - University of South AlabamaSachindra R. Joshi - University of South AlabamaMrigendra M. Bastola - University of South AlabamaJared M. McLendon - University of South AlabamaMasahiko Oka - University of South AlabamaKaren A. Fagan - University of South AlabamaIvan F. McMurtry - University of South Alabama
- Resource Type
- Journal article
- Publication Details
- Pulmonary circulation, Vol.6(3), pp.369-380
- Publisher
- SAGE Publications
- DOI
- 10.1086/687766
- PMID
- 27683614
- PMCID
- PMC5019090
- ISSN
- 2045-8940
- eISSN
- 2045-8940
- Number of pages
- 12
- Grant note
- University of South Alabama American Heart Association (11POST7720023) Departments of Internal Medicine and Pharmacology and the Center for Lung Biology
- Language
- English
- Date published
- 09/2016
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Internal Medicine
- Record Identifier
- 9984618506302771
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