Activation of Sphingosine Kinase-1 Reverses the Increase in Lung Vascular Permeability Through Sphingosine-1-Phosphate Receptor Signaling in Endothelial Cells

AbstractThe enzyme sphingosine kinase-1 (SK1) promotes the formation of sphingosine-1-phosphate (S1P), which is an important survival factor for endothelial cells (EC). Modest increases in intracellular SK1 activity in the EC are known to confer a survival advantage upon the cells. Here, we investigated the effects of more dramatic increases in intracellular SK1 in the EC. We found that these cells show reduced cell survival under conditions of stress, enhanced caspase-3 activity, cell cycle inhibition, and cell-cell junction disruption. We propose that alterations in the phosphorylation state of the enzyme may explain the differential effects on the phenotype with modest versus high levels of enforced expression of SK1. Our results suggest that SK1 activity is subject to control in the EC, and that this control may be lost in conditions involving vascular regression.

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Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720

Journal of Biological Chemistry ◽

10.1074/jbc.m406512200 ◽

2004 ◽

Vol 279 (50) ◽

pp. 52487-52492 ◽

Cited By ~ 339

Author(s):

Maria L. Allende ◽

Teiji Sasaki ◽

Hiromichi Kawai ◽

Ana Olivera ◽

Yide Mi ◽

...

Keyword(s):

Vascular Development ◽

Sphingosine Kinase ◽

Sphingosine Kinase 1 ◽

Cellular Functions ◽

Lymphocyte Trafficking ◽

Signaling Molecule ◽

Physiological Functions ◽

Sphingosine 1 Phosphate ◽

Sphingosine Kinases ◽

S1p Receptor

Sphingosine-1-phosphate (S1P), a lipid signaling molecule that regulates many cellular functions, is synthesized from sphingosine and ATP by the action of sphingosine kinase. Two such kinases have been identified, SPHK1 and SPHK2. To begin to investigate the physiological functions of sphingosine kinase and S1P signaling, we generated mice deficient in SPHK1.Sphk1null mice were viable, fertile, and without any obvious abnormalities. Total SPHK activity in mostSphk1-/-tissues was substantially, but not completely, reduced indicating the presence of multiple sphingosine kinases. S1P levels in most tissues from theSphk1-/- mice were not markedly decreased. In serum, however, there was a significant decrease in the S1P level. Although S1P signaling regulates lymphocyte trafficking, lymphocyte distribution was unaffected in lymphoid organs ofSphk1-/- mice. The immunosuppressant FTY720 was phosphorylated and elicited lymphopenia in theSphk1null mice showing that SPHK1 is not required for the functional activation of this sphingosine analogue prodrug. The results with theseSphk1null mice reveal that some key physiologic processes that require S1P receptor signaling, such as vascular development and proper lymphocyte distribution, can occur in the absence of SPHK1.

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Impaired Sphingosine-1-Phosphate Synthesis Induces Preeclampsia by Deactivating Trophoblastic YAP (Yes-Associated Protein) Through S1PR2 (Sphingosine-1-Phosphate Receptor-2)-Induced Actin Polymerizations

Hypertension ◽

10.1161/hypertensionaha.121.18363 ◽

2021 ◽

Author(s):

Jiujiang Liao ◽

Yangxi Zheng ◽

Mingyu Hu ◽

Ping Xu ◽

Li Lin ◽

...

Keyword(s):

Actin Polymerization ◽

Sphingosine Kinase ◽

Actin Dynamics ◽

Extravillous Trophoblast ◽

Trophoblast Invasion ◽

Hippo Signaling ◽

Dependent Manner ◽

Sphingosine Kinase 1 ◽

Sphingosine 1 Phosphate

Incomplete spiral artery remodeling, caused by impaired extravillous trophoblast invasion, is a fundamental pathogenic process associated with malplacentation and the development of preeclampsia. Nevertheless, the mechanisms controlling this regulation of trophoblast invasion are largely unknown. We report that sphingosine-1-phosphate synthesis and expression is abundant in healthy trophoblast, whereas in pregnancies complicated by preeclampsia the placentae are associated with reduced sphingosine-1-phosphate and lower SPHK1 (sphingosine kinase 1) expression and activity. In vivo inhibition of sphingosine kinase 1 activity during placentation in pregnant mice led to decreased placental sphingosine-1-phosphate production and defective placentation, resulting in a preeclampsia phenotype. Moreover, sphingosine-1-phosphate increased HTR8/SVneo (immortalized trophoblast cells) cell invasion in a Hippo-signaling–dependent transcriptional coactivator YAP (Yes-associated protein) dependent manner, which is activated by S1PR2 (sphingosine-1-phosphate receptor-2) and downstream RhoA/ROCK induced actin polymerization. Mutation-based YAP-5SA demonstrated that sphingosine-1-phosphate activation of YAP could be either dependent or independent of Hippo signaling. Together, these findings suggest a novel pathogenic pathway of preeclampsia via disrupted sphingosine-1-phosphate metabolism and signaling-induced, interrupted actin dynamics and YAP deactivation; this may lead to potential novel intervention targets for the prevention and management of preeclampsia.

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Sphingosine‐1‐Phosphate‐Mediated Endothelial Cell Motility Is Regulated by S1P1 Receptor, Lipid Phosphate Phosphatase‐1 and Sphingosine Kinase 1

The FASEB Journal ◽

10.1096/fasebj.20.4.a483-a ◽

2006 ◽

Vol 20 (4) ◽

Author(s):

Irina Gorshkova ◽

Evgeny Berdyshev ◽

Bahman Saatian ◽

Yutong Zhao ◽

Srikanth Pendyala ◽

...

Keyword(s):

Endothelial Cell ◽

Cell Motility ◽

Sphingosine Kinase ◽

Sphingosine Kinase 1 ◽

S1p1 Receptor ◽

Sphingosine 1 Phosphate ◽

Lipid Phosphate

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Overexpression of Sphingosine Kinase-1 and Sphingosine-1-Phosphate Receptor-3 in Severe Plasmodium falciparum Malaria with Pulmonary Edema

BioMed Research International ◽

10.1155/2020/3932569 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Parnpen Viriyavejakul ◽

Chuchard Punsawad

Keyword(s):

Plasmodium Falciparum ◽

Epithelial Cells ◽

Lung Injury ◽

Pulmonary Edema ◽

Sphingosine Kinase ◽

Alveolar Epithelial Cells ◽

Sphingosine Kinase 1 ◽

Expression Levels ◽

Alveolar Epithelial ◽

Sphingosine 1 Phosphate

Pulmonary edema (PE) is a major cause of pulmonary manifestations of severe Plasmodium falciparum malaria and is usually associated with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The sphingosine kinase-1 (SphK-1)/sphingosine-1-phosphate receptor-3 (S1PR-3) pathway has recently been reported to affect the pathogenesis of lung injury, but the expression of these proteins in the lungs of severe P. falciparum malaria patients has not been investigated. The cellular expression of SphK-1 and S1PR-3 in lung tissues from autopsied patients with P. falciparum malaria was investigated using immunohistochemistry (IHC). Lung tissues from patients who died of severe P. falciparum malaria were classified into two groups based on histopathological findings: those with PE (18 patients) and those without PE (non-PE, 19 patients). Ten samples of normal lung tissues were used as the control group. The protein expression levels of SphK-1 and S1PR-3 were significantly upregulated in endothelial cells (ECs), alveolar epithelial cells, and alveolar macrophages (AMs) in the lungs of severe P. falciparum malaria patients with PE compared to those in the non-PE and control groups (all p<0.001). In addition, the SphK-1 and S1PR-3 expression levels were significantly positively correlated in pulmonary ECs (rs=0.922, p<0.001), alveolar epithelial cells (rs=0.995, p<0.001), and AMs (rs=0.969, p<0.001). In conclusion, both the SphK-1 and S1PR-3 proteins were overexpressed in the lung tissues of severe P. falciparum malaria patients with PE, suggesting that SphK-1 and S1PR-3 mediate the pathogenesis of PE in severe malaria. Targeting the regulation of SphK-1 and/or S1PR-3 may be an approach to treat pulmonary complications in severe P. falciparum patients.

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