Characterization of the Anticoagulant and Antithrombotic Properties of the Sphingosine 1-Phosphate Mimetic FTY720

Zhao, Zhenyu; Huo, Zhijun; Li, Chunlei; Wang, Zhiyong

doi:10.1159/000448837

Cited by 10 publications

(8 citation statements)

References 21 publications

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“…Rats were administered a single FTY720 ip injection at a dose of 2.5 mg/kg. This dose is sufficient to affect S1PR signaling 34 and is below higher functional doses (e.g. 10 mg/kg) that have been reported in the absence of adverse side effects 30,35 .…”

Section: Timecourse Of Fty720 and Fty720-p Concentrations In Plasma Following Ip Injectionmentioning

confidence: 83%

FTY720 (Fingolimod), a modulator of sphingosine-1-phosphate receptors, increases baseline hypothalamic-pituitary adrenal axis activity and alters behaviors relevant to affect and anxiety

Corbett

Luz

Sotuyo

et al. 2021

Preprint

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FTY720 (fingolimod) is an analog of sphingosine, a ubiquitous sphingolipid. Phosphorylated FTY720 (FTY720-P) non-selectively binds to sphingosine-1-phosphate receptors (S1PRs) and regulates multiple cellular processes including cell proliferation, inflammation, and angiogenesis. We recently demonstrated that S1PR3 expression in the medial prefrontal cortex (mPFC) of rats promotes stress resilience and that S1PR3 expression in blood may serve as a biomarker for PTSD. Here we investigate the effects of FTY720 in regulating the stress response. We found that single and repeated intraperitoneal injections of FTY720 increased baseline plasma adrenocorticotropic hormone (ACTH) and corticosterone concentrations. FTY720 also mitigated restraint-induced increases in ACTH and corticosterone. FTY720 reduced social anxiety- and despair-like behavior as assessed by increased social interaction time and reduced time spent immobile in the Porsolt forced swim test. In blood, FTY720 administration reduced lymphocyte and reticulocyte counts, but raised erythrocyte counts. FTY720 also reduced mRNA of angiopoietin 1, endothelin 1, plasminogen 1, Vegf-B, and Mmp2 in the medial prefrontal cortex, suggesting that FTY720 reduced angiogenesis. The antidepressant-like and anxiolytic-like effects of FTY720 may be attributed to reduced angiogenesis as increased stress-induced blood vessel density in the brain contributes to depression- and anxiety-like behavior in rats. Together, these results suggest that S1PRs regulate baseline HPA axis activity but reduces social anxiety and despair providing further evidence that S1PRs are important and novel regulators of stress-related functions.

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Section: Timecourse Of Fty720 and Fty720-p Concentrations In Plasma Following Ip Injectionmentioning

confidence: 83%

FTY720 (Fingolimod), a modulator of sphingosine-1-phosphate receptors, increases baseline hypothalamic-pituitary adrenal axis activity and alters behaviors relevant to affect and anxiety

Corbett

Luz

Sotuyo

et al. 2021

Preprint

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“…FTY720, a novel immunosuppressant, has unique pharmacological action, and its chemical structure and action mechanism differ from those of the existing immunosuppressants. FTY720 acts directly on lymphocytes, and exerts immunosuppressive effects . Therefore, FTY720 was once widely recognized in the field of transplantation immune tolerance.…”

Section: Discussionmentioning

confidence: 99%

The sphingosine 1‐phosphate receptor agonist FTY720 interfered the distribution of dendritic cell and induced the maternal‐fetal immune tolerance

Xiong

Liu

et al. 2018

J of Cellular Biochemistry

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“…Furthermore, SPL irreversibly degrades the lipid signaling molecule S1P, which has recently emerged as a critical mediator linking the coagulation factor system to vascular inflammation 47 and has been implicated in various cardiovascular events such as myocardial infarction and stroke. 48 49 50 Thus, it would be of interest to seek replication and also to investigate associations between rare variants in SGPL1 and cardiovascular diseases. However, as the MAF is as low as 0.02 to 0.03%, this will require very large datasets genotyped with rare variant information (e.g.…”

Section: Discussionmentioning

confidence: 99%

A Genome-wide Study of Common and Rare Genetic Variants Associated with Circulating Thrombin Activatable Fibrinolysis Inhibitor

et al. 2018

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Thrombin-activatable fibrinolysis inhibitor (TAFI) plays a central role in haemostasis, and plasma TAFI concentrations are heritable. Candidate gene studies have identified several variants within the gene encoding TAFI, CPB2 , that explain part of the estimated heritability. Here, we describe an exploratory genome-wide association study to identify novel variants within and outside of the CPB2 locus that influence plasma concentrations of intact TAFI and/or the extent of TAFI activation (measured by released TAFI activation peptide, TAFI-AP) amongst 3,260 subjects from Southern Sweden. We also explored the role of rare variants on the HumanExome BeadChip. We confirmed the association with previously reported common variants in CPB2 for both intact TAFI and TAFI-AP, and discovered novel associations with variants in putative CPB2 enhancers. We identified a gene-based association with intact TAFI at CPB2 ( P SKAT-O = 2.8 × 10 −8 ), driven by two novel rare nonsynonymous single nucleotide polymorphisms (SNPs; I420N and D177G). Carriers of the rare variant of D177G (rs140446990; MAF 0.2%) had lower intact TAFI and TAFI-AP concentrations compared with non-carriers (intact TAFI, geometric mean 53 vs. 78%, P T-test = 5 × 10 −7 ; TAFI-AP 63 vs. 99%, P T-test = 7.2 × 10 −4 ). For TAFI-AP, we identified a genome-wide significant association at an intergenic region of chromosome 3p14.1 and five gene-based associations (all P SKAT-O < 5 × 10 −6 ). Using well-characterized assays together with a genome-wide association study and a rare-variant approach, we verified CPB2 to be the primary determinant of TAFI concentrations and identified putative secondary loci (candidate variants and genes) associated with intact TAFI and TAFI-AP that require independent validation.

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Characterization of the Anticoagulant and Antithrombotic Properties of the Sphingosine 1-Phosphate Mimetic FTY720

Cited by 10 publications

References 21 publications

FTY720 (Fingolimod), a modulator of sphingosine-1-phosphate receptors, increases baseline hypothalamic-pituitary adrenal axis activity and alters behaviors relevant to affect and anxiety

FTY720 (Fingolimod), a modulator of sphingosine-1-phosphate receptors, increases baseline hypothalamic-pituitary adrenal axis activity and alters behaviors relevant to affect and anxiety

The sphingosine 1‐phosphate receptor agonist FTY720 interfered the distribution of dendritic cell and induced the maternal‐fetal immune tolerance

A Genome-wide Study of Common and Rare Genetic Variants Associated with Circulating Thrombin Activatable Fibrinolysis Inhibitor

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