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; Горшкова, И. А.; 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 F.

doi:10.1164/rccm.201401-0121oc

Cited by 119 publications

(199 citation statements)

References 59 publications

(62 reference statements)

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“…Both K0 ITSNþ/À mice, on a 129SV/J genetic background that is more resistant to PAH, 26 and KD ITSN on a CD1 genetic background (data not shown) were used. Despite their reported resistance to PAH, ).…”

Section: A Murine Model Of Plexiform Arteriopathymentioning

confidence: 99%

Modulation of Intersectin-1s Lung Expression Induces Obliterative Remodeling and Severe Plexiform Arteriopathy in the Murine Pulmonary Vascular Bed

Patel

Predescu

Bardita

et al. 2017

The American Journal of Pathology

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Murine models of pulmonary arterial hypertension (PAH) that recapitulate the plexiform and obliterative arteriopathy seen in PAH patients and help in defining the molecular mechanisms involved are missing. Herein, we investigated whether intersectin-1s (ITSN) deficiency and prolonged lung expression of an ITSN fragment with endothelial cell (EC) proliferative potential (EH ITSN ), present in the lungs of PAH animal models and human patients, induce formation of plexiform/obliterative lesions and defined the molecular mechanisms involved. ITSN-deficient mice (knockout/heterozygous and knockdown) were subjected to targeted lung delivery of EH ITSN via liposomes for 20 days. Immunohistochemistry and histological and morphometric analyses revealed a twofold increase in proliferative ECs and a 1.35-fold increase in proliferative a-smooth muscle actinepositive cells in the lungs of ITSNdeficient mice, transduced with the EH ITSN relative to wild-type littermates. Treated mice developed severe medial wall hypertrophy, intima proliferation, and various forms of obliterative and plexiformlike lesions in pulmonary arteries, similar to PAH patients. Hemodynamic measurements indicated modest increases in the right ventricular systolic pressure and right ventricle hypertrophy. Transcriptional and protein assays of lung tissue indicated p38 MAPK -dependent activation of Elk-1 transcription factor and increased expression of c-Fos gene. This unique murine model of PAH-like plexiform/obliterative arteriopathy induced via a two-hit pathophysiological mechanism without hypoxia provides novel druggable targets to ameliorate and, perhaps, reverse the EC plexiform phenotype in severe human PAH. Pulmonary arterial hypertension (PAH) is a severe human disease characterized by narrowing of the small pulmonary arteries, leading to a progressive increase in pulmonary vascular resistance, which frequently leads to right-sided heart failure and death.1e3 A common histological finding in patients with severe PAH is the presence of plexiform lesions that obliterate the small to mid-sized pulmonary arterioles. 4,5 The plexiform pulmonary vascular lesions found at branching points in the small pulmonary arterioles are lumen-obliterating, glomeruloid-like vascular structures, predominantly composed of actively dividing and phenotypically abnormal apoptosis-resistant endothelial cells (ECs).6,7 The cellular and molecular mechanisms responsible for the development of plexiform lesions are poorly understood.Recent evidence suggests the involvement of inflammatory mechanisms in the development of PAH. 8 Studies have indicated that inflammation associated with human PAH Supported by NIH grants R01 HL089462 (S.P.) and R01 HL0127022 (S.P.).Disclosures: None declared.

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Section: A Murine Model Of Plexiform Arteriopathymentioning

confidence: 99%

Modulation of Intersectin-1s Lung Expression Induces Obliterative Remodeling and Severe Plexiform Arteriopathy in the Murine Pulmonary Vascular Bed

Patel

Predescu

Bardita

et al. 2017

The American Journal of Pathology

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“…1032-1043) examined the SphK1/S1P pathway in PH and show that it promotes pulmonary arterial smooth muscle cell (PASMC) proliferation (20). This finding was identified using a combination of rodent models of hypoxia-mediated PH, human explanted lungs, and isolated human PASMCs.…”

Section: Is Pulmonary Hypertension a Metabolic Disease?mentioning

confidence: 99%

Is Pulmonary Hypertension a Metabolic Disease?

Barnes

Dweik²

2014

Am J Respir Crit Care Med

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“…4,5 Physiological levels of circulating S1P are vasculoprotective, whereas abnormal activation of SphK/S1P signaling is associated with diseases such as cancer, fibrosis, diabetes, and hypertension. [6][7][8][9][10] At high cellular or tissue levels, S1P is a proproliferative, antiapoptotic, promigratory, profibrotic, and proinflammatory signaling molecule. 11 SphK activity and S1P production are stimulated by numerous signals, including growth factors, cytokines, mitogens, and G protein-coupled receptor agonists.…”

mentioning

confidence: 99%

Sphingosine‐1‐Phosphate is Involved in the Occlusive Arteriopathy of Pulmonary Arterial Hypertension

et al. 2016

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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.Keywords: occlusive lesions, S1P, pulmonary, cardiac. Pulmonary arterial hypertension (PAH) remains debilitating and deadly despite advanced and expensive medical treatment. 1 Its pathogenic mechanisms have not been fully identified and therapeutically targeted. A limitation in the current treatment of patients with PAH is the inability of prostanoids, endothelin receptor blockers, phosphodiesterase inhibitors, or their various combinations to reverse the pulmonary arteriopathy. 2,3 An effective strategy in the development of more efficacious therapy would be to identify the molecular determinants of the arterial wall remodeling.Sphingosine-1-phosphate (S1P) is a biologically active lipid synthesized intracellularly by sphingosine kinase 1 (SphK1) and SphK2 and degraded by S1P lyase and various phosphatases. It is released by endothelial cells, red blood cells, activated platelets, and monocytes and has regulatory roles in several physiological and pathological processes. 4,5 Physiological levels of circulating S1P are vasculoprotective, whereas abnormal activation of SphK/S1P signaling is associated with diseases such as cancer, fibrosis, diabetes, and hypertension. [6][7][8][9][10] At high cellular or tissue levels, S1P is a proproliferative, antiapoptotic, promigratory, profibrotic, and proinflammatory signaling molecule. 11 SphK activity and S1P production are stimulated by numerous signals, including growth factors, cytokines, m...

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

Abstract: 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.

Cited by 119 publications

References 59 publications

Modulation of Intersectin-1s Lung Expression Induces Obliterative Remodeling and Severe Plexiform Arteriopathy in the Murine Pulmonary Vascular Bed

Modulation of Intersectin-1s Lung Expression Induces Obliterative Remodeling and Severe Plexiform Arteriopathy in the Murine Pulmonary Vascular Bed

Is Pulmonary Hypertension a Metabolic Disease?

Sphingosine‐1‐Phosphate is Involved in the Occlusive Arteriopathy of Pulmonary Arterial Hypertension

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