Sphingosine-1-Phosphate Induces Pulmonary Vascular Inflammation by Activating the Canonical NF-κB and Inflammasome Pathway

S1P exerts a diverse set of vascular responses, and PAR-2 has been shown to be involved in vascular inflammation as well as in other inflammatory-based diseases. In the present study, we demonstrate that S1P-mediated vascular effect involves PAR-2 activation.

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PET Study of Sphingosine-1-Phosphate Receptor 1 Expression in Response to Vascular Inflammation in a Rat Model of Carotid Injury

Molecular Imaging ◽

10.1177/1536012116689770 ◽

2017 ◽

Vol 16 ◽

pp. 153601211668977 ◽

Cited By ~ 11

Author(s):

Hui Liu ◽

Hongjun Jin ◽

Xuyi Yue ◽

Junbin Han ◽

Pamela Baum ◽

...

Keyword(s):

Rat Model ◽

Vascular Inflammation ◽

Carotid Injury ◽

Sphingosine 1 Phosphate

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Sphingosine-1-Phosphate and Its Receptors: A Mutual Link between Blood Coagulation and Inflammation

Mediators of Inflammation ◽

10.1155/2015/831059 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 29

Author(s):

Shailaja Mahajan-Thakur ◽

Andreas Böhm ◽

Gabriele Jedlitschky ◽

Karsten Schrör ◽

Bernhard H. Rauch

Keyword(s):

Intracellular Signaling ◽

Inflammatory Responses ◽

Vascular Inflammation ◽

Expression Patterns ◽

Coagulation Factor ◽

Cell Types ◽

Vascular Wall ◽

Coagulation System ◽

Cellular Effects ◽

Sphingosine 1 Phosphate

Sphingosine-1-phosphate (S1P) is a versatile lipid signaling molecule and key regulator in vascular inflammation. S1P is secreted by platelets, monocytes, and vascular endothelial and smooth muscle cells. It binds specifically to a family of G-protein-coupled receptors, S1P receptors 1 to 5, resulting in downstream signaling and numerous cellular effects. S1P modulates cell proliferation and migration, and mediates proinflammatory responses and apoptosis. In the vascular barrier, S1P regulates permeability and endothelial reactions and recruitment of monocytes and may modulate atherosclerosis. Only recently has S1P emerged as a critical mediator which directly links the coagulation factor system to vascular inflammation. The multifunctional proteases thrombin and FXa regulate local S1P availability and interact with S1P signaling at multiple levels in various vascular cell types. Differential expression patterns and intracellular signaling pathways of each receptor enable S1P to exert its widespread functions. Although a vast amount of information is available about the functions of S1P and its receptors in the regulation of physiological and pathophysiological conditions, S1P-mediated mechanisms in the vasculature remain to be elucidated. This review summarizes recent findings regarding the role of S1P and its receptors in vascular wall and blood cells, which link the coagulation system to inflammatory responses in the vasculature.

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HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1to limit vascular inflammation

Science Signaling ◽

10.1126/scisignal.aaa2581 ◽

2015 ◽

Vol 8 (389) ◽

pp. ra79-ra79 ◽

Cited By ~ 145

Author(s):

Sylvain Galvani ◽

Marie Sanson ◽

Victoria A. Blaho ◽

Steven L. Swendeman ◽

Hideru Obinata ◽

...

Keyword(s):

Endothelial Cell ◽

Vascular Inflammation ◽

Cell Receptor ◽

Sphingosine 1 Phosphate ◽

Biased Agonist

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Abstract 15736: The Sphk1/s1p Signaling Axis Regulates Pulmonary Vascular Inflammation by Activating Nf-kb and Nlrp3 Inflammasome

Circulation ◽

10.1161/circ.142.suppl_3.15736 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Yang Bai ◽

Alan de Brito Carneiro ◽

Angelia Lockett ◽

Marta T Gomes ◽

Nicole Jones ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Vascular Inflammation ◽

Inflammasome Activation ◽

Western Blots ◽

Caspase 1 ◽

Signaling Axis ◽

Intracellular Expression ◽

Sphingosine 1 Phosphate ◽

Pulmonary Arterial ◽

The Impact

Rationale: Pulmonary vascular inflammation is activated during the development of pulmonary arterial hypertension (PAH). Sphingosine kinase 1 (Sphk1) catalyzes the formation of sphingosine-1-phosphate (S1P), which has been shown to promote inflammation by activating nuclear factor kappa B (NF-κB) and the nucleotide oligomerization domain-like receptor 3 (NLRP3) inflammasome. However, the impact of S1P on NLRP3 inflammasome activation in PAH is unknown. Here, we tested whether Sphk1/S1P regulates pulmonary vascular inflammation via activating NF-κB and the NLRP3 inflammasome. Methods: Human pulmonary arterial smooth muscle cells (PASMCs) and endothelial cells (PAECs) were treated with S1P or were exposed to hypoxia. Sphk1 plasmid or siRNA was used to increase and decrease Sphk1/S1P levels, respectively. Activation of NF-κB signaling and the NLRP3 inflammasome (increased NLRP3, cleaved caspase-1, IL-1β and IL-18) were detected by western blots or real-time PCR. ELISA was used to measure secretion of IL-1β. Results: S1P treatment led to a biphasic phosphorylation and degradation of IκBα accompanied by increased phosphorylation and expression of NF-κB in PASMCs. S1P treatment also resulted in increased expression of inflammasome mediators, NLRP3 and cleaved caspase-1, enhanced intracellular expression of IL-1b and IL-18, and higher levels of secreted IL-1β compared to controls. Notably, over expression of Sphk1 in PASMCs led to increased NF-κB and NLRP3 expression, whereas suppression of Sphk1 expression reduced NLRP3, cleavage of IL-1β and IL-18 expression and phosphorylation of NF-κB. Similar phenomena with respect to inflammasome activation and IL-1β secretion was observed in PASMCs exposed to hypoxia. Increased NF-κB and NLRP3 activation, cleavage of caspase-1 were also observed in S1P treated PAECs, however no changes in IL-1β secretion levels were detected. Conclusion: These findings suggest that S1P induces pulmonary vascular pro-inflammatory signaling via activation of NF-κB and the NLRP3 inflammasome, and that the S1P/Sphk1 signaling axis may be involved in this context. Activation of the inflammasome may be an important mechanism underlying PAH pathogenesis, targeting of which may be exploited for the treatment of PAH.

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Abstract 335: Atheroma-specific Delivery of Synthetic High-density Lipoprotein Containing Sphingosine-1-phosphate for Modulation of Vascular Inflammation.

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.335 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Emily E Morin ◽

Yanhong Guo ◽

Rui Kuai ◽

Gergely Lautner ◽

Mark E Meyerhoff ◽

...

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Vascular Inflammation ◽

The Body ◽

Saline Control ◽

No Production ◽

No Release ◽

Sphingosine 1 Phosphate ◽

Anti Inflammatory

Introduction: Sphingosine-1-phosphate (S1P) is a potent anti-inflammatory signaling lipid carried in the body by circulating HDL. HDL has been shown to exhibit anti-inflammatory activities through activation of endothelial nitric oxide synthase (eNOS) and subsequent production and release of nitric oxide (NO) by endothelial cells. Objective: The aim of this study is to use synthetic HDL particles to selectively deliver S1P to the site of arterial plaques in order to exert anti-inflammatory activity and modulate the progression of atherosclerosis. Methods/Results: Synthetic HDL (sHDL) particles were prepared using the ApoA1 mimetic peptide 22A (PVLDLFRELLNELLEALKQKLK), dipalmitoylphosphatidylcholine (DPPC) and sphingomyelin. We also prepared sHDL containing either the hydrophobic dye, DiD, or S1P to assess the capability of sHDL to effectively reach atheroma site and induce nitric oxide (NO) release, respectively. The purity of all particles was determined to be > 97% and average particle size was 9.6 ± 0.4 nm for all preparations. To measure sHDL accumulation in the plaque, ApoE -/- mice were intravenously injected with 0.2 mg/kg HDL-DiD. Whole aortas were excised and analysed by IVUS imaging system, revealing significant accumulation of sHDL-DiD in the atherosclerotic lesions. We then tested the ability of sHDL to deliver S1P in vitro and induce NO production by treating human umbilical vein endothelial cells (HUVEC) with 1 mg/mL of 22A-DPPC-sHDL containing 0, 0.05, 0.5, or 5 nmol/mL of S1P using free 22A peptide (1 mg/mL) and saline as controls, and analyzing media by ozone chemiluminescence. Blank sHDL particles increased NO production two-fold over controls (0.27 ± 0.02 μM for 22A-DPPC-sHDLDL, 0.13 ± 0.01 μM PBS and 0.14 ± 0.02 μM for 22A peptide), while HDL-S1P further increased NO release: 0.35 ± 0.03, 0.44 ± 0.01, and 0.59 ± 0.01 μM for HDL with 0.05, 0.5, and 5 nmol/mL S1P, respectively. Conclusions: Our studies show that HDL is capable of delivering hydrophobic cargo to atherosclerotic plaques, making HDL a promising platform to deliver S1P for modulation vascular inflammation and atherosclerosis. In vitro studies have revealed that HDL-S1P is able to increase NO production 2 to 4-fold over saline control setting the basis for future in vivo studies.

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Protease-Activated Receptor PAR-4: An Inducible Switch between Thrombosis and Vascular Inflammation?

Thrombosis and Haemostasis ◽

10.1160/th17-03-0219 ◽

2017 ◽

Vol 117 (11) ◽

pp. 2013-2025 ◽

Cited By ~ 12

Author(s):

Anke Fender ◽

Bernhard Rauch ◽

Tobias Geisler ◽

Karsten Schrör

Keyword(s):

Vascular Inflammation ◽

Cellular Growth ◽

Transcriptional Level ◽

Redox Stress ◽

Promising Target ◽

Cardiovascular Patients ◽

Independent Functions ◽

Sphingosine 1 Phosphate ◽

Protease Activated Receptor 1

AbstractThrombin triggers activation of platelets through protease-activated receptor 1 (PAR-1) and PAR-4. Both receptors are widely expressed and exert multiple platelet-independent functions. PAR signalling contributes to healing responses after injury, by promoting cytokine activity and cellular growth and mobility. Uncontrolled PAR activation, however, can prevent timely resolution of inflammation, enhance thrombogenic endothelial function and drive adverse remodelling. The specific role of PAR-4 in thromboinflammatory vascular disease has been largely underestimated, given the relatively limited expression of PAR-4 in non-platelet cells under healthy conditions. However, unlike PAR-1, PAR-4 expression adapts dynamically to numerous stimuli associated with thromboinflammation, including thrombin, angiotensin II, sphingosine-1-phosphate (S1P), high glucose and redox stress, suggesting expression is switched on ‘at need’. Prostacyclin negatively regulates PAR-4 expression at the post-transcriptional level, which may serve to fine-tune thrombin responses and limit these to the injury site. PAR-4 elicits inflammatory, mitogenic and proliferative actions not only in response to thrombin but also to numerous other inflammatory proteases, and can cross-talk with other receptor systems such as S1P and adenosine receptors. Accordingly, PAR-4 has emerged as a candidate player in vessel disease and cardiac post-infarction remodelling. Currently, PAR-4 is a particularly promising target for safer anti-thrombotic therapies. Recent studies with the PAR-4 antagonist BMS-986120 lend support to the concept that selective antagonism of PAR-4 may offer both an effective and safe anti-thrombotic therapy in the acute thrombotic setting as well as an anti-inflammatory strategy to prevent long-term progressive atherosclerotic disease in high-risk cardiovascular patients.

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Erratum for the Research Article: “HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1to limit vascular inflammation” by S. Galvani, M. Sanson, V. A. Blaho, S. L. Swendeman, H. Conger, B. Dahlbäck, M. Kono, R. L. Proia, J. D. Smith, T. Hla

Science Signaling ◽

10.1126/scisignal.aad6067 ◽

2015 ◽

Vol 8 (400) ◽

pp. er8-er8

Keyword(s):

Endothelial Cell ◽

Vascular Inflammation ◽

Cell Receptor ◽

Research Article ◽

Sphingosine 1 Phosphate ◽

Biased Agonist

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Relevance and potential of sphingosine-1-phosphate in vascular inflammatory disease

Biological Chemistry ◽

10.1515/bc.2008.165 ◽

2008 ◽

Vol 389 (11) ◽

Cited By ~ 15

Author(s):

Markus van der Giet ◽

Markus Tölle ◽

Burkhard Kleuser

Keyword(s):

Inflammatory Disease ◽

Therapeutic Option ◽

Vascular Inflammation ◽

Vascular Diseases ◽

Receptor Activation ◽

Pathological Feature ◽

Sphingosine 1 Phosphate ◽

S1p Receptor ◽

Anti Inflammatory

Abstract The typical pathological feature of atherosclerosis is inflammation. In the last years, it has become evident that inhibition of inflammation is one important therapeutic option in atherosclerosis. Recently, sphingolipid sphingosine-1-phosphate (S1P) was identified as a crucial molecule with potent anti-inflammatory properties. Indeed, S1P activates various G protein-coupled receptors, namely S1P1–S1P5. In the vasculature, mainly S1P1–3 receptors are present. FTY720, after phosphorylation to FTY720-P, is an orally active S1P mimetic. FTY720 has been developed for therapy in the field of autoimmune diseases and organ transplantation. In analogy to S1P, FTY720 shows potent anti-inflammatory effects and several groups have tested the in vivo effects of FTY720 on the progression of inflammatory vascular diseases. They could show that S1P receptor activation might lead to a partial inhibition of the progression of atherosclerotic lesions. S1P receptor activation therefore might be a concept for anti-inflammatory drug treatment. However, it is not clear how S1P and FTY720 exactly act on vascular inflammation. This review article gives a brief overview over the known actions of S1P in vascular inflammatory disease.

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