In vitro and in vivo modulation of vascular barrier integrity by sphingosine 1-phosphate: mechanistic insights

2005 ◽  
Vol 17 (2) ◽  
pp. 131-139 ◽  
Author(s):  
Bryan J. McVerry ◽  
Joe G.N. Garcia
Keyword(s):  
Barrier Integrity ◽  
Sphingosine 1 Phosphate ◽  
Vascular Barrier Integrity

Abstract 606: Antithrombin Nanoparticle Therapy Safely Restores Endothelial Barrier Integrity and Reduces Vessel Hypercoagulability in Atherosclerotic Mice

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Rohun U Palekar ◽  
Andrew P Jallouk ◽  
Hua Pan ◽  
Samuel A Wickline
Keyword(s):  
Endothelial Barrier ◽  
Thrombin Inhibitor ◽  
Saline Control ◽  
Resonance Spectroscopy ◽  
Therapeutic Effects ◽  
Thrombotic Risk ◽  
Barrier Integrity ◽  
Vascular Barrier Integrity

Introduction: Thrombin plays a major role in regulating signaling pathways responsible for atherogenesis, hypercoagulability and plaque permeability. Herein, we report the therapeutic effects of perfluorocarbon core nanoparticles (PFC-NP) conjugated to the thrombin inhibitor D-phenylalanyl-L-prolyl-L-chloromethylketone (PPACK-NP) on vascular barrier integrity and hypercoagulability. Methods and Results: ApoE-/- mice were fed a Western diet for 4 months, and received 3 doses/week of saline or 1 ml/kg PPACK-NP for the final month of feeding. Endothelial barrier integrity was assessed by quantifying the ability of atherosclerotic aortas to take up circulating semipermeable PFC-NP (~250 nm diameter). Whole aortas (arch to iliacs) were excised after 2 hour in vivo exposure to PFC-NP and underwent fluorine magnetic resonance spectroscopy ( 19 F-MRS) to quantify plaque-permeating PFC-NP. 19 F-MRS data revealed a significant decrease in plaque permeability to PFC-NP after PPACK-NP treatment compared to saline control (0.081 ± 0.011 μl PFC-NP/g aorta, N = 5 vs. 0.122 ± 0.014 μl PFC-NP/g aorta, N = 8 for PPACK-NP treated vs. saline control, p = 0.027). To assess hypercoagulability, carotid artery injury was induced photochemically to measure the time to complete occlusion as an index of thrombotic risk. Occlusion times were significantly prolonged with PPACK-NP treatment compared to untreated mice (49.8 ± 6.7 min, N = 5 vs. 26.1 ± 4.6 min, N = 9 for PPACK-NP treated vs. saline control, p = 0.019), indicating a decrease in vessel hypercoagulability after therapeutic intervention. Furthermore, PPACK-NP treatment of human aortic endothelial cells in vitro abrogated thrombin-mediated activation of surface PAR-1 receptors as measured by flow cytometry, suggesting a potential dual role for PPACK-NP in the localized modulation of both thrombosis and PAR-1 signaling. Moreover, this sustained therapeutic benefit is obtained without systemic anticoagulation as all clotting parameters and bleeding times are completely normalized within 60 minutes after i.v. injection. Conclusion: Thrombin inhibition with PPACK-NP is effective in restoring vascular barrier integrity and reducing focal thrombotic risk within a single month without incurring bleeding risk.

Role of sphingosine-1 phosphate in the enhancement of endothelial barrier integrity by platelet-released products

2003 ◽  
Vol 285 (1) ◽  
pp. L258-L267 ◽  
Author(s):  
Kane L. Schaphorst ◽  
Eddie Chiang ◽  
Keri N. Jacobs ◽  
Ari Zaiman ◽  
Viswanathan Natarajan ◽  
...  
Keyword(s):  
Electrical Resistance ◽  
Human Platelets ◽  
Lipid Mediator ◽  
Permeability Barrier ◽  
Barrier Dysfunction ◽  
Barrier Integrity ◽  
Enhancing Effect ◽  
Sphingosine 1 Phosphate

In vitro and in vivo evidence indicates that circulating platelets affect both vascular integrity and hemostasis. How platelets enhance the permeability barrier of the vascular endothelium is not well understood. We measured the effect of isolated human platelets on human pulmonary artery endothelial cell (EC) barrier integrity by monitoring transmonolayer electrical resistance. EC barrier function was significantly increased by the addition of platelets (∼40% maximum, 2.5 × 106platelets/ml). Platelet supernatants, derived from 2.5 × 106platelets/ml, reproduced the barrier enhancement and reversed the barrier dysfunction produced by the edemagenic agonist thrombin, which implicates a soluble barrier-promoting factor. The barrier-enhancing effect of platelet supernatants was heat stable but was attenuated by either charcoal delipidation (suggesting a vasoactive lipid mediator) or pertussis toxin, implying involvement of a Giα-coupled receptor signal transduction pathway. Sphingosine-1-phosphate (S1P), a sphingolipid that is released from activated platelets, is known to ligate G protein-coupled EC differentiation gene (EDG) receptors, increase EC electrical resistance, and reorganize the actin cytoskeleton (Garcia JG, Liu F, Verin AD, Birukova A, Dechert MA, Gerthoffer WT, Bamberg JR, and English D. J Clin Invest 108: 689–701, 2001). Infection of EC with an adenoviral vector expressing an antisense oligonucleotide directed against EDG-1 but not infection with control vector attenuated the barrier-enhancing effect of both platelet supernatants and S1P. These results indicate that a major physiologically relevant vascular barrier-protective mediator produced by human platelets is S1P.

scholarly journals SMYD3 promotes hepatocellular carcinoma progression by methylating S1PR1 promoters

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Heyun Zhang ◽  
Zhangyu Zheng ◽  
Rongqin Zhang ◽  
Yongcong Yan ◽  
Yaorong Peng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathways ◽  
Histone Methylation ◽  
Cell Growth And Migration ◽  
Histone 3 ◽  
Sphingosine 1 Phosphate ◽  
And Migration ◽  
Proliferation And Migration

AbstractHepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. SET and MYND domain-containing protein 3 (SMYD3) has been shown to promote the progression of various types of human cancers, including liver cancer; however, the detailed molecular mechanism is still largely unknown. Here, we report that SMYD3 expression in HCC is an independent prognostic factor for survival and promotes the proliferation and migration of HCC cells. We observed that SMYD3 upregulated sphingosine-1-phosphate receptor 1 (S1PR1) promoter activity by methylating histone 3 (H3K4me3). S1PR1 was expressed at high levels in HCC samples, and high S1PR1 expression was associated with shorter survival. S1PR1 expression was also positively correlated with SMYD3 expression in HCC samples. We confirmed that SMYD3 promotes HCC cell growth and migration in vitro and in vivo by upregulating S1PR1 expression. Further investigations revealed that SMYD3 affects critical signaling pathways associated with the progression of HCC through S1PR1. These findings strongly suggest that SMYD3 has a crucial function in HCC progression that is partially mediated by histone methylation at the downstream gene S1PR1, which affects key signaling pathways associated with carcinogenesis and the progression of HCC.

scholarly journals Galectin-1 Promotes Metastasis in Gastric Cancer Through a Sphingosine-1-Phosphate Receptor 1-Dependent Mechanism

2018 ◽  
Vol 51 (1) ◽  
pp. 11-30 ◽  
Author(s):  
Xiaolan You ◽  
Yuanjie Wang ◽  
Jian Wu ◽  
Qinghong Liu ◽  
Dehu Chen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Clinical Samples ◽  
Mesenchymal Transition ◽  
Sphingosine 1 Phosphate ◽  
Enhanced Expression ◽  
Emt Markers ◽  
Tgf Β1 ◽  
Dependent Mechanism

Background/Aims: Increased expression of galectin-1 (Gal-1) in gastric cancer (GC) promotes metastasis and correlates with poor prognosis. The mechanisms by which Gal-1 promotes GC metastasis remain unknown. Methods: Gal-1and Sphingosine-1-phosphate receptor 1 (S1PR1) were determined by immunohistochemistry(IHC) and quantitative real time polymerase chain reaction (qRT-PCR) in GC specimens. Stably transfected Gal-1 or S1PR1 into SGC7901 and MGC-803 cells, western blot and invasion assays in vitro and nude mice tumorigenicity in vivo were also employed. Results: Overexpression of Gal-1 enhanced expression of S1PR1 in SGC-7901 cells, and increased cell invasion, while knockdown Gal-1 in MGC-803 cells reduced S1PR1 expression and diminished invasion. Simultaneous knockdown of Gal-1 and overexpression of S1PR1 in MGC803 cells rescued invasive ability of MGC803 cells. S1PR1 was associated with expression of epithelial-to-mesenchymal transition (EMT) markers in vitro and in clinical samples. EMT induced in MGC-803 cells by TGF-β1 was accompanied by S1PR1 activation, while knockdown of S1PR1 reduced response to TGF-β1, suggest that Gal-1 promotes GC invasion by activating EMT through a S1PR1-dependent mechanism. Overexpression of S1PR1 promoted subcutaneous xenograft growth and pulmonary metastases, and enhanced expression of EMT markers. Conclusion: Galectin-1 promotes metastasis in gastric cancer through a S1PR1- dependent mechanism, our results indicate that targeting S1PR1 may be a novel strategy to treat GC metastasis.

scholarly journals HO-1/CO Maintains Intestinal Barrier Integrity through NF-κB/MLCK Pathway in Intestinal HO-1-/- Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Zhenling Zhang ◽  
Lijing Zhang ◽  
Qiuping Zhang ◽  
Bojia Liu ◽  
Fang Li ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Intestinal Barrier ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Barrier Integrity ◽  
Tnf Α ◽  
Intestinal Barrier Integrity ◽  
Deficient Mice

Background. Intestinal barrier injury is an important contributor to many diseases. We previously found that heme oxygenase-1 (HO-1) and carbon monoxide (CO) protect the intestinal barrier. This study is aimed at elucidating the molecular mechanisms of HO-1/CO in barrier loss. Materials and Methods. We induced gut leakiness by injecting carbon tetrachloride (CCl4) to wildtype or intestinal HO-1-deficient mice. In addition, we administrated tumor necrosis factor-α (TNF-α) to cells with gain- or loss-of-HO-1 function. The effects of HO-1/CO maintaining intestinal barrier integrity were investigated in vivo and in vitro. Results. Cobalt protoporphyrin and CO-releasing molecule-2 alleviated colonic mucosal injury and TNF-α levels; upregulated tight junction (TJ) expression; and inhibited epithelial IκB-α degradation and phosphorylation, NF-κB p65 phosphorylation, long MLCK expression, and MLC-2 phosphorylation after administration of CCl4. Zinc protoporphyrin completely reversed these effects. These findings were further confirmed in vitro, using Caco-2 cells with gain- or loss-of-HO-1-function after TNF-α. Pretreated with JSH-23 (NF-κB inhibitor) or ML-7 (long MLCK inhibitor), HO-1 overexpression prevented TNF-α-induced TJ disruption, while HO-1 shRNA promoted TJ damage even in the presence of JSH-23 or ML-7, thus suggesting that HO-1 dependently protected intestinal barrier via the NF-κB p65/MLCK/p-MLC-2 pathway. Intestinal HO-1-deficient mice further demonstrated the effects of HO-1 in maintaining intestinal barrier integrity and its relative mechanisms. Alleviated hepatic fibrogenesis and serum ALT levels finally confirmed the clinical significance of HO-1/CO repairing barrier loss in liver injury. Conclusion. HO-1/CO maintains intestinal barrier integrity through the NF-κB/MLCK pathway. Therefore, the intestinal HO-1/CO-NF-κB/MLCK system is a potential therapeutic target for diseases with a leaky gut.

scholarly journals Sphingosine 1-phosphate in inflammation

2020 ◽  
Vol 4 (6) ◽  
Author(s):  
Lijuan Li ◽  
Lixia An ◽  
Lifang Li ◽  
Yongjuan Zhao
Keyword(s):  
Plasma Membrane ◽  
Drug Targets ◽  
Therapeutic Potential ◽  
Cell Types ◽  
In Vivo Models ◽  
Integral Role ◽  
Sphingosine 1 Phosphate ◽  
And Migration

Sphingolipids are formed via the metabolism of sphingomyelin, aconstituent of the plasma membrane, or by denovosynthesis. Enzymatic pathways result in the formation of several different lipid mediators, which are known to have important roles in many cellular processes, including proliferation, apoptosis and migration. Several studies now suggest that these sphingolipid mediators, including ceramide, ceramide 1-phosphate and sphingosine 1-phosphate (S1P), are likely to have an integral role in in?ammation. This can involve, for example, activation of pro-in?ammatory transcription factors in different cell types and induction of cyclooxygenase-2, leading to production of pro-in?ammatory prostaglandins. The mode of action of each sphingolipid is different. Increased ceramide production leads to the formation of ceramide-rich areas of the membrane, which may assemble signalling complexes, whereas S1P acts via high-af?nity G-protein-coupled S1P receptors on the plasma membrane. Recent studies have demonstrated that in vitro effects of sphingolipids on in?ammation can translate into in vivo models. This review will highlight the areas of research where sphingolipids are involved in in?ammation and the mechanisms of action of each mediator. In addition, the therapeutic potential of drugs that alter sphingolipid actions will be examined with reference to disease states, such as asthma and in?ammatory bowel disease, which involve important in?ammatory components. A signi?cant body of research now indicates that sphingolipids are intimately involved in the in?ammatory process and recent studies have demonstrated that these lipids, together with associated enzymes and receptors, can provide effective drug targets for the treatment of pathological in?ammation.

Abstract 23: Microrna302-367 Sphingosine 1 Phosphate Receptor 1 Pathway Prevents Tumor Growth via Restricting Angiogenesis and Enhancing Vascular Stability

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Jinjiang Pi ◽  
Ting Tao ◽  
Tao Zhuang ◽  
Huimin Sun ◽  
Xiaoli Chen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Growth ◽  
Ex Vivo ◽  
Downstream Target ◽  
Sprouting Angiogenesis ◽  
Pathological Angiogenesis ◽  
Vascular Stability ◽  
Sphingosine 1 Phosphate

Angiogenic hypersprouting and leaky immature vessels of pathological angiogenesis are essential for tumor growth. MicroRNAs have unique therapeutic advantages by targeting multiple pathways of tumor-associated angiogenesis, but the function of individual miRNAs in angiogenesis and tumors has not yet been fully evaluated. Here, we show that miR302-367 elevation in endothelial cells reduces retina sprouting angiogenesis and promotes vascular stability in vivo, ex vivo and in vitro. Erk1/2 are identified as direct targets of miR302-367, and down-regulation of Erk1/2 upon miR302-367 elevation in endothelial cells increases the expression of Klf2 and in turn S1pr1 and its downstream target VE-cadherin, suppressing angiogenesis and improving vascular stability. Conversely, both pharmacological blockade and genetic deletion of S1pr1 in endothelial cells reverse the anti-angiogenic and vascular stabilizing effect of miR302-367 in mice. Pathological angiogenesis in tumors shares features of developmental angiogenesis, and endothelial specific elevation of miR302-367 reduces tumor growth by restricting sprout angiogenesis and decreasing vascular permeability via the same Erk1/2-Klf2-S1pr1 pathways. In conclusion, miR302-367 regulation of an Erk1/2-Klf2-S1pr1 pathway in the endothelium advances our understanding of angiogenesis, meanwhile also provides opportunities for therapeutic intervention of tumor growth.

Sphingosine‐1‐phosphate (S1P) induces potent anti‐inflammatory effects in vitro and in vivo by S1P receptor 4‐mediated suppression of 5‐lipoxygenase activity

2018 ◽  
Vol 33 (2) ◽  
pp. 1711-1726 ◽  
Author(s):  
Jasmin Fettel ◽  
Benjamin Kühn ◽  
Nathalie A. Guillen ◽  
Duran Sürün ◽  
Marcus Peters ◽  
...  
Keyword(s):  
Lipoxygenase Activity ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
Anti Inflammatory

The sphingosine-1-phosphate derivative NHOBTD inhibits angiogenesis both in vitro and in vivo

2011 ◽  
Vol 413 (2) ◽  
pp. 189-193 ◽  
Author(s):  
Beom Seok Kim ◽  
Hyomi Park ◽  
Seung Hwan Ko ◽  
Won Koo Lee ◽  
Ho Jeong Kwon
Keyword(s):  
Sphingosine 1 Phosphate

Effects of flavonoids on intestinal inflammation, barrier integrity and changes in gut microbiota during diet-induced obesity

2016 ◽  
Vol 29 (2) ◽  
pp. 234-248 ◽  
Author(s):  
Katherine Gil-Cardoso ◽  
Iris Ginés ◽  
Montserrat Pinent ◽  
Anna Ardévol ◽  
Mayte Blay ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Gut Microbiota ◽  
Intestinal Inflammation ◽  
Mucosal Barrier ◽  
Low Grade ◽  
Protective Effects ◽  
Barrier Integrity ◽  
Diet Induced Obesity

AbstractDiet-induced obesity is associated with low-grade inflammation, which, in most cases, leads to the development of metabolic disorders, primarily insulin resistance and type 2 diabetes. Although prior studies have implicated the adipose tissue as being primarily responsible for obesity-associated inflammation, the latest discoveries have correlated impairments in intestinal immune homeostasis and the mucosal barrier with increased activation of the inflammatory pathways and the development of insulin resistance. Therefore, it is essential to define the mechanisms underlying the obesity-associated gut alterations to develop therapies to prevent and treat obesity and its associated diseases. Flavonoids appear to be promising candidates among the natural preventive treatments that have been identified to date. They have been shown to protect against several diseases, including CVD and various cancers. Furthermore, they have clear anti-inflammatory properties, which have primarily been evaluated in non-intestinal models. At present, a growing body of evidence suggests that flavonoids could exert a protective role against obesity-associated pathologies by modulating inflammatory-related cellular events in the intestine and/or the composition of the microbiota populations. The present paper will review the literature to date that has described the protective effects of flavonoids on intestinal inflammation, barrier integrity and gut microbiota in studies conducted using in vivo and in vitro models.

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