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

2008 ◽  
Vol 389 (11) ◽  
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.

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

scholarly journals Heart rate reduction with ivabradine promotes shear stress-dependent anti-inflammatory mechanisms in arteries

2016 ◽  
Vol 116 (07) ◽  
pp. 181-190 ◽  
Author(s):  
Luong Le ◽  
Hayley Duckles ◽  
Torsten Schenkel ◽  
Marwa Mahmoud ◽  
Jordi Tremoleda ◽  
...  
Keyword(s):  
Heart Rate ◽  
Shear Stress ◽  
Carotid Arteries ◽  
Vascular Inflammation ◽  
Protective Effects ◽  
En Face ◽  
Inflammatory Activation ◽  
Anti Inflammatory ◽  
Stress Dependent

SummaryBlood flow generates wall shear stress (WSS) which alters endothelial cell (EC) function. Low WSS promotes vascular inflammation and atherosclerosis whereas high uniform WSS is protective. Ivabradine decreases heart rate leading to altered haemodynamics. Besides its cardio-protective effects, ivabradine protects arteries from inflammation and atherosclerosis via unknown mechanisms. We hypothesised that ivabradine protects arteries by increasing WSS to reduce vascular inflammation. Hypercholesterolaemic mice were treated with ivabradine for seven weeks in drinking water or remained untreated as a control. En face immunostaining demonstrated that treatment with ivabradine reduced the expression of pro-inflammatory VCAM-1 (p<0.01) and enhanced the expression of anti-inflammatory eNOS (p<0.01) at the inner curvature of the aorta. We concluded that ivabradine alters EC physiology indirectly via modulation of flow because treatment with ivabradine had no effect in ligated carotid arteries in vivo, and did not influence the basal or TNFα-induced expression of inflammatory (VCAM-1, MCP-1) or protective (eNOS, HMOX1, KLF2, KLF4) genes in cultured EC. We therefore considered whether ivabradine can alter WSS which is a regulator of EC inflammatory activation. Computational fluid dynamics demonstrated that ivabradine treatment reduced heart rate by 20 % and enhanced WSS in the aorta. In conclusion, ivabradine treatment altered haemodynamics in the murine aorta by increasing the magnitude of shear stress. This was accompanied by induction of eNOS and suppression of VCAM-1, whereas ivabradine did not alter EC that could not respond to flow. Thus ivabradine protects arteries by altering local mechanical conditions to trigger an anti-inflammatory response.

Abstract 529: Statin Therapy Decreases Vascular Inflammation and Prolongs Patency in Murine Arteriovenous Fistula

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Jie Cui ◽  
Harkamal S Jhajj ◽  
Chase W Kessinger ◽  
Jason McCarthy ◽  
Farouc A Jaffer
Keyword(s):  
Blood Flow ◽  
Statin Therapy ◽  
Inflammatory Cell ◽  
Vascular Inflammation ◽  
Neointimal Hyperplasia ◽  
Venous Outflow ◽  
Statin Group ◽  
Cellular Inflammation ◽  
Anti Inflammatory

Background: AVFs are the lifeline of dialysis patients, but can often occlude. The most common cause of AVF failure is inflammation-driven neointimal hyperplasia and thrombosis. Here, we investigated whether statin therapy with well-recognized anti-inflammatory properties can improve murine AVF patency, and further assessed the anti-inflammatory effects. Methods: One week prior to AVF creation, mice were randomized to oral atorvastatin 1.14mg/kg/day or control 100ul PBS (both n=10), administered by daily gavage. AVF were created using an end-to-side internal jugular vein and carotid artery anastomosis. AVF blood flow was measured (Transonic blood flow probe) at day 0 and weekly thereafter until occlusion (blood flow < 0.1ml/min). On day 6, CLIO-VT680, an inflammatory cell-targeted fluorescent nanoparticle, was injected intravenously (10mg/kg). 24 hours later, in vivo survival epifluorescence molecular imaging was performed to visualize inflammatory cell in the AVF venous outflow limb. Histopathological assessment of AVF was performed in on day 7 and 14 mice (6 statin each, 6 control each) to assess venous outflow area, AVF scarring via collagen, and adventitial macrophage content. Results: At day 7, the in vivo venous outflow cellular inflammation signal (CLIO-VT680 TBR) was significantly lower in statin-treated mice (3.5±0.16 vs 4.5±0.5 PBS, p=0.02). Adventitial macrophage content was significantly lower in statin group at day 14 (p=0.01). Positive AVF remodeling, a desirable feature for clinical AVF patency, was higher in the statin group as compared to the PBS group (p=0.02 at week 1, p=0.002 at week 2). In vivo, statin-treated animals exhibited greater AVF blood flow (BF) preservation from day 7 to day 14 (ΔAVF BF +0.14±0.2 ml/min vs. -0.79±0.32 ml/min PBS, p=0.02). The ΔAVF BF from day 7 to day 14 correlated inversely and significantly with the day 7 CLIO-VT680 cellular inflammation (r=-0.56, p=0.02), indicating that baseline inflammation may predict AVF failure. Kaplan Meier survival analysis showed median AVF patency in mice treated with statin was 28 days compared to 14 days in PBS treated group (p<0.05). Conclusion: Statin therapy prolongs AVF patency and preserves AVF blood flow in association with diminished AVF cellular inflammation.

Abstract 11890: S100A8/A9 is Increased in Psoriasis Serum, Relates to Vascular Diseases and Activates Human Endothelial Cells

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Heather Teague ◽  
Qimin Ng ◽  
Monica Purmalek ◽  
Balaji Natarajan ◽  
Taufiq Salahuddin ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Fdg Pet ◽  
Vascular Inflammation ◽  
Vascular Diseases ◽  
Aortic Endothelial Cells ◽  
Pet Ct ◽  
Calcified Plaque ◽  
Fdg Pet Ct ◽  
Psoriasis Severity

Introduction: Psoriasis is a chronic inflammatory disorder of the skin affecting 2-4% of the population and is associated with an increased risk of cardiovascular events, specifically myocardial infarction. Methods: In a large, ongoing prospective cohort study of psoriasis and cardiovascular diseases (NCT01778569), we studied a consecutive sample (n=100) and aimed to investigate the potential role that S100A8/A9 may have in linking psoriasis to CV disease measured by FDG PET CT and coronary CTA. Furthermore, we conducted in vitro experiments on human aortic endothelial cells (ECs) to examine whether treatement with S100A9 activates these cells. We hypothesized that S100A8/A9 would relate to psoriasis severity, relate to in vivo vascular inflammation by FDG PET CT, non-calcified burden of coronary disease by CCTA and increase endothelial cell activation. Results: We observed that the S100A8/A9 heterodimer was elevated in serum (mean psoriasis: 2019 ± 100.1; non-psoriasis: 1634 ± 160.7; p = 0.02), correlating both with psoriasis severity score (adjusted β = 0.53, p = 0.02) and overall aortic vascular inflammation measured by FDG PET CT (adjusted β = 0.48, p = 0.02) beyond the Framingham Risk Score. Additionally, we found that S100A8/A9 was associated with direct coronary atherosclerosis measured by coronary CTA demonstrating an increase in total (β = 0.16, p = 0.04) and non-calcified plaque burden (β = 0.23, p = 0.003) but not dense calcified burden. When EC's were treated with S100A9, ICAM1, E-Selectin and VCAM1 gene expression levels increased 10-fold (p = 0.001), 86-fold (P = 0.007) and 20-fold (p = 0.0002) respectively compared to the untreated human aortic endothelial cells. Conclusions: S100A8/A9 related to psoriasis severity, in vivo vascular inflammation, non-calcified plaque in the coronary arteries and EC activation. These findings suggest this protein may play a role in linking psoriasis to CVD and a role in early atherosclerotic plaque formation. Ongoing studies aim to elucidate the source of S100A8/A9 in the blood and to characterize the signaling pathway utilized by S100A8/A9 to understand whether this pathway is broadly applicable to vascular diseases associated with chronic inflammation.

Abstract 13667: Programming to S1PR1 + Endothelial Cell Population Promotes the Restoration of Vascular Integrity in vivo

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Zahid Akhter ◽  
Jagdish Chandra Joshi ◽  
Vijay Avin Balaji Ragunathrao ◽  
Richard L Proia ◽  
Asrar B Malik ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Lung Injury ◽  
Endothelial Permeability ◽  
Vascular Diseases ◽  
Mechanistic Study ◽  
Rna Seq ◽  
Vascular Integrity ◽  
Injured Lung ◽  
Sphingosine 1 Phosphate

Introduction: Increased endothelial permeability and failure to repair is the hallmark of several vascular diseases including acute lung injury (ALI). However, little is known about the intrinsic pathways that activate the endothelial cell (EC) regenerative programs facilitating thereby tissue repair. Studies have invoked a crucial role of sphingosine-1-phosphate (S1P) in resolving endothelial hyperpermeability through activation of the G-protein coupled receptor, sphingosine-1-phosphate receptor 1 (S1PR1). Hypothesis: We postulate that S1PR1 + EC serve as an endogenous means to prevent endothelial injury. Methods: Studies were made using EC-S1PR1 null mice and S1PR1-GFP reporter mice to trace the generation and characteristics of S1PR1 + EC by exploiting immuno-histochemical analysis and FACS. RNA-seq analysis was performed to identify the genetic signature of S1PR1 + EC. Combination of genetic and pharmacological strategies were included for mechanistic study. Transplantation of S1PR1 + EC and edema measurement was performed in EC-S1PR1 null mice. Results: We observed in a mouse model of endotoxemia that LPS via generation of S1P induced the programming of S1PR1 lo EC to S1PR1 + EC, comprising 80% of lung EC. Their generation preceded the vascular repair phase and these cells were required for reestablishing the endothelial barrier function. Thus, conditional deletion of S1PR1 in EC spontaneously increased lung vascular permeability. RNA-seq analysis of S1PR1 + EC showed enrichment of genes regulating S1P synthesis and transport, sphingosine kinase 1 (SPHK1) and SPNS2, respectively, as well as transcription factors EGR1 and STAT3. EGR1 and STAT3 were essential for transcribing SPHK1 and SPNS2, respectively to increase S1P concentration that served to amplify S1PR1 + EC transition. Transplantation of S1PR1 + EC into injured lung vasculature of EC-S1PR1 -/- mice restored endothelial integrity. Conclusions: Findings illustrate that generation of a specialized S1PR1 + EC population has the potential to activate key endothelial regenerative program mediating vascular endothelial repair raising the possibility of activating this pathway to restore vascular homeostasis in inflammatory lung injury.

scholarly journals Combining Ceftriaxone with Doxycycline and Daptomycin Reduces Mortality, Neuroinflammation, Brain Damage, and Hearing Loss in Infant Rat Pneumococcal Meningitis

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Lukas Muri ◽  
Michael Perny ◽  
Jonas Zemp ◽  
Denis Grandgirard ◽  
Stephen L. Leib
Keyword(s):  
Adjuvant Therapy ◽  
Antibiotic Therapy ◽  
Brain Damage ◽  
Pneumococcal Meningitis ◽  
Therapeutic Option ◽  
Case Fatality ◽  
Content Type ◽  
Anti Inflammatory

ABSTRACTDespite appropriate antibiotic therapy, pneumococcal meningitis (PM) is associated with a case fatality rate of up to 30% in high-income countries. Survivors often suffer from severe lifelong disabilities. An excessive inflammatory reaction drives the pathophysiology, leading to brain damage and neurologic sequelae. We aimed to improve the outcome of experimental PM by simultaneously targeting different pathophysiological mechanisms with combined adjunctive therapies previously shown to be neuroprotective.In vitro, the anti-inflammatory effects of doxycycline and daptomycin were evaluated on primary rat astroglial cells stimulated withStreptococcus pneumoniae. Eleven-day-old infant Wistar rats were infected intracisternally withS. pneumoniaeand randomized for treatment with ceftriaxone or combination adjuvant therapy consisting of ceftriaxone, daptomycin, and doxycycline. During acute PM, combined-adjuvant therapy with ceftriaxone, daptomycin, and doxycycline increased the survival rate from 64.1% to 85.8% (P < 0.01) and alleviated weight loss compared to ceftriaxone monotherapy (P < 0.01). Levels of inflammatory cytokines were significantly reduced by combined-adjuvant therapyin vitro(P < 0.0001) and in cerebrospinal fluidin vivo(P < 0.05). In infected animals treated with combined adjunctive therapy, cortical damage was significantly reduced (P < 0.05), and animals showed a trend toward better hearing capacity 3 weeks after the infection (P = 0.089), an effect which was significant in mildly infected animals (48 decibels [dB] versus 67.22 dB;P < 0.05). These mildly infected animals showed significantly reduced cochlear fibrous occlusion (P < 0.01). By combining nonbacteriolytic daptomycin and anti-inflammatory doxycycline with ceftriaxone, the previously reported beneficial effects of the drugs were cumulated and identified the triple-antibiotic therapy as a promising therapeutic option for pediatric PM.

scholarly journals Copper chelation by tetrathiomolybdate inhibits lipopolysaccharide-induced inflammatory responses in vivo

2011 ◽  
Vol 301 (3) ◽  
pp. H712-H720 ◽  
Author(s):  
Hao Wei ◽  
Balz Frei ◽  
Joseph S. Beckman ◽  
Wei-Jian Zhang
Keyword(s):  
Inflammatory Responses ◽  
Vascular Inflammation ◽  
Surrogate Marker ◽  
Transition Metal Ions ◽  
Intercellular Adhesion Molecule ◽  
Etiologic Factor ◽  
Copper Chelation ◽  
Tnf Α ◽  
Anti Inflammatory

Redox-active transition metal ions, such as iron and copper, may play an important role in vascular inflammation, which is an etiologic factor in atherosclerotic vascular diseases. In this study, we investigated whether tetrathiomolybdate (TTM), a highly specific copper chelator, can act as an anti-inflammatory agent, preventing lipopolysaccharide (LPS)-induced inflammatory responses in vivo. Female C57BL/6N mice were daily gavaged with TTM (30 mg/kg body wt) or vehicle control. After 3 wk, animals were injected intraperitoneally with 50 μg LPS or saline buffer and killed 3 h later. Treatment with TTM reduced serum ceruloplasmin activity by 43%, a surrogate marker of bioavailable copper, in the absence of detectable hepatotoxicity. The concentrations of both copper and molybdenum increased in various tissues, whereas the copper-to-molybdenum ratio decreased, consistent with reduced copper bioavailability. TTM treatment did not have a significant effect on superoxide dismutase activity in heart and liver. Furthermore, TTM significantly inhibited LPS-induced inflammatory gene transcription in aorta and heart, including vascular and intercellular adhesion molecule-1 (VCAM-1 and ICAM-1, respectively), monocyte chemotactic protein-1 (MCP-1), interleukin-6, and tumor necrosis factor (TNF)-α (ANOVA, P < 0.05); consistently, protein levels of VCAM-1, ICAM-1, and MCP-1 in heart were also significantly lower in TTM-treated animals. Similar inhibitory effects of TTM were observed on activation of nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) in heart and lungs. Finally, TTM significantly inhibited LPS-induced increases of serum levels of soluble ICAM-1, MCP-1, and TNF-α (ANOVA, P < 0.05). These data indicate that copper chelation with TTM inhibits LPS-induced inflammatory responses in aorta and other tissues of mice, most likely by inhibiting activation of the redox-sensitive transcription factors, NF-κB and AP-1. Therefore, copper appears to play an important role in vascular inflammation, and TTM may have value as an anti-inflammatory or anti-atherogenic agent.

scholarly journals Mesenchymal Stem Cell Therapy Ameliorates Metabolic Dysfunction and Restores Fertility in a PCOS Mouse Model Through Interleukin-10

2021 ◽  
Author(s):  
Rishi Man Chugh ◽  
Hang-soo Park ◽  
Abdeljabar El Andaloussi ◽  
Amro Elsharoud ◽  
Sahar Esfandyari ◽  
...  
Keyword(s):  
Gene Expression ◽  
Polycystic Ovary ◽  
Therapeutic Option ◽  
Interleukin 10 ◽  
Reproductive Age ◽  
Metabolic Dysfunction ◽  
Mesenchymal Stem Cell Therapy ◽  
Anti Inflammatory

Abstract Background: Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in reproductive-age women. Excessive inflammation and elevated androgen production from ovarian theca cells are key features of PCOS. Human bone marrow mesenchymal stem cells (BM-hMSC) and their secreted factors (secretome) exhibit robust anti-inflammatory capabilities in various biological systems. We evaluated the therapeutic efficacy of BM-hMSC and its secretome in both in vitro and in vivo PCOS models.Methods: For in vitro experiment, we treated conditioned media from BM-hMSC to androgen producing H293R cells, and analyzed androgen producing gene expression. For in vivo experiment, BM-hMSC were implanted into Letrozole (LTZ) induced mouse PCOS model. BM-hMSC effect in androgen producing cells or PCOS model mice was assessed by monitoring cell proliferation (immunohistochemistry), steroidogenic gene expression (quantitative real-time polymerase chain reaction [qRT-PCR] and Western blot, animal tissue assay (H&E staining), and fertility by pup delivery.Results: BM-hMSC significantly downregulate steroidogenic gene expression, curb inflammation, and restore fertility in treated PCOS animals. The anti-inflammatory cytokine interleukin-10 (IL-10) played a key role in mediating the effects of BM-hMSC in our PCOS models. We demonstrated that BM-hMSC treatment was improve in metabolic and reproductive markers in our PCOS model and able to restore fertility. Conclusion: Our study demonstrates for the first time the efficacy of intra-ovarian injection of BM-hMSC or its secretome to treat PCOS-related phenotypes, including both metabolic and reproductive dysfunction. This approach may represent a novel therapeutic option for women with PCOS. Our results suggest that BM-hMSC can reverse PCOS-induced inflammation through IL-10 secretion. BM-hMSC might be a novel and robust therapeutic approach for PCOS treatment.

scholarly journals Stauntonia hexaphylla leaf extract (YRA-1909) suppresses inflammation by modulating Akt/NF-κB signaling in lipopolysaccharide-activated peritoneal macrophages and rodent models of inflammation

2021 ◽  
Author(s):  
Jaeyong Kim ◽  
Gyuok Lee ◽  
Huwon Kang ◽  
Ji-Seok Yoo ◽  
Yongnam Lee ◽  
...  
Keyword(s):  
Leaf Extract ◽  
Inflammatory Diseases ◽  
Vascular Diseases ◽  
Peritoneal Macrophages ◽  
Inflammatory Activity ◽  
Dependent Manner ◽  
Inflammatory Stimuli ◽  
Anti Inflammatory

Background: Inflammation is emerging as a key contributor to many vascular diseases and furthermore plays a major role in autoimmune diseases, arthritis, allergic reactions, and cancer. Lipopolysaccharide (LPS), which is a component constituting the outer membrane of Gram-negative bacteria, is commonly used for an inflammatory stimuli to mimic inflammatory diseases. Nuclear factor-kappa B (NF-κB) is a transcription factor and regulates gene expression particularly related to the inflammatory process. Stauntonia hexaphylla (Lardizabalaceae) is widely used as a traditional herbal medicine for rheumatism and osteoporosis and as an analgesic, sedative, and diuretic in Korea, Japan, and China. Objective: The purpose of this study was to investigate the anti-inflammatory activity of YRA-1909, the leaf aqueous extract of Stauntonia hexaphylla using LPS-activated rat peritoneal macrophages and rodent inflammation models. Results: YRA-1909 inhibited the LPS-induced nitric oxide (NO) and proinflammatory cytokine production in rat peritoneal macrophages without causing cytotoxicity and reduced inducible NO synthase and prostaglandin E2 levels without affecting the cyclooxygenase-2 expression. YRA-1909 also prevented the LPS-stimulated Akt and NF-κB phosphorylation and reduced the carrageenan-induced hind paw edema, xylene-induced ear edema, acetic acid-induced vascular permeation, and cotton pellet-induced granuloma formation in a dose-dependent manner in mice and rats. Conclusions: S. hexaphylla leaf extract YRA-1909 had anti-inflammatory activity in vitro and in vivo that involves modulation of Akt/NF-κB signaling. Thus, YRA-1909 is safe and effective for the treatment of inflammation.

scholarly journals Sphingosine-1-phosphate receptor 1 reporter mice reveal receptor activation sites in vivo

2014 ◽  
Vol 124 (5) ◽  
pp. 2076-2086 ◽  
Author(s):  
Mari Kono ◽  
Ana E. Tucker ◽  
Jennifer Tran ◽  
Jennifer B. Bergner ◽  
Ewa M. Turner ◽  
...  
Keyword(s):  
Receptor Activation ◽  
Reporter Mice ◽  
Sphingosine 1 Phosphate
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