Targeting Sphingosine Kinase 1 for the Treatment of Pulmonary Arterial Hypertension

Yang, Kan; Jiang, Kaixuan; Xu, Zhengwen; Song, Yali

doi:10.4155/fmc-2019-0130

Cited by 6 publications

(5 citation statements)

References 98 publications

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“…SphK1/S1P has been reported to mediate TGF-β1-induced proliferation in rat PASMCs (Wang et al, 2019), however, we did not observe a significant pro-proliferative effect of TGF-β1 in human PASMC (Figure S4). This highlights potential differences between the responses of rat and human PASMCs to the same stimuli.…”

Section: Discussioncontrasting

confidence: 74%

“…It required deletion of SphK1 and SphK2 to completely abolish the production of S1P and inhibit the effect of S1P (Meng, Yuan, & Lee, 2011;Mizugishi et al, 2005;Xiong et al, 2013). This could explain the less significant inhibitory effect of PF-543 on TGF-β-induced αSMA expression, since PF-543 might not fully block the function of SphK2 at 10 µM (Yang, Jiang, Xu, Song, & Wang, 2019). Overall, these findings still suggest that SphK1 is important for regulating TGF-β-induced αSMA expression and that CNN1 expression is not completely dependent on S1P signaling.…”

Section: Sphk1 Inhibitors Reduce Tgf-β-induced αSma Expressionmentioning

confidence: 99%

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Transforming Growth Factor β1 Increases Expression of Contractile Genes in Human Pulmonary Arterial Smooth Muscle Cells by Potentiating Sphingosine-1-Phosphate Signaling

Lisabeth

Neubig

2021

Mol Pharmacol

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Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure and carries a very poor prognosis. Understanding PAH pathogenesis is needed to support the development of new therapeutic strategies. TGF-β drives vascular remodeling and increases vascular resistance by regulating differentiation and proliferation of smooth muscle cells (SMCs). Also, sphingosine-1-phosphate (S1P) has been implicated in PAH but the relation between these two signaling mechanisms is not well understood. Here, we characterize the signaling networks downstream of TGF-β in human pulmonary arterial smooth muscle cells (HPASMCs) which involves SMAD signaling as well as Rho GTPases. Activation of Rho GTPases regulates myocardin-related transcription factor (MRTF) and serum response factor (SRF) transcription activity and results in upregulation of contractile gene expression. Our genetic and pharmacologic data show that in HPASMCs, upregulation of alpha smooth muscle actin (αSMA) and calponin (CNN1) by TGF-β is dependent on both SMAD and Rho/MRTF-A/SRF transcriptional mechanisms.The kinetics of TGF-β-induced myosin-light chain 2 (MLC2) phosphorylation, a measure of RhoA activation, is slow, as is regulation of the Rho/MRTF/SRF-induced αSMA expression.These results suggest that TGF-β1 activates Rho/pMLC2 through an indirect mechanism which was confirmed by sensitivity to cycloheximide treatment. As a potential mechanism for this indirect action, TGF-β1 upregulates mRNA for sphingosine kinase (SphK1), the enzyme that produces sphingosine-1-phosphate (S1P), an upstream Rho activator as well as mRNA levels of the S1P Receptor 3 (S1PR3). A SphK1 inhibitor and S1PR3 inhibitors (PF543 and TY52156/VPC23019) reduce TGF-β1-induced αSMA upregulation. Overall, we propose a model where TGF-β1 activates Rho/MRTF-A/SRF by potentiating an autocrine/paracrine S1P signaling mechanism through SphK1 and S1PR3.

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Section: Discussioncontrasting

confidence: 74%

Section: Sphk1 Inhibitors Reduce Tgf-β-induced αSma Expressionmentioning

confidence: 99%

Transforming Growth Factor β1 Increases Expression of Contractile Genes in Human Pulmonary Arterial Smooth Muscle Cells by Potentiating Sphingosine-1-Phosphate Signaling

Lisabeth

Neubig

2021

Mol Pharmacol

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“…It has been proved that SphK1 is involved in the occurrence of pulmonary arterial hypertension (PAH) based on the over-expression of SphK1 in vascular smooth muscle cells (VSMC) and lymphocytes of patients with PAH, and the symptoms of PAH were alleviated in SphK1 knockout mice rather than SphK2 ( Pyne and Pyne, 2017 ; Yang et al, 2019 ). Thus, SphK1/S1P signaling is a novel pathway in the inflammatory mechanism of PAH.…”

Section: Role Of Sphingosine Kinase 1 In Inflammatory Immune Related-diseasesmentioning

confidence: 99%

Therapeutic Potential of SphK1 Inhibitors Based on Abnormal Expression of SphK1 in Inflammatory Immune Related-Diseases

Hong

Deng

2021

Front. Pharmacol.

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Sphingosine kinase 1(SphK1) a key enzyme that catalyzes the conversion of sphingosine (Sph) to sphingosine 1-phosphate (S1P), so as to maintain the dynamic balance of sphingolipid-rheostat in cells and participate in cell growth and death, proliferation and migration, vasoconstriction and remodeling, inflammation and metabolism. The normal expression of SphK1 maintains the balance of physiological and pathological states, which is reflected in the regulation of inflammatory factor secretion, immune response in traditional immune cells and non-traditional immune cells, and complex signal transduction. However, abnormal SphK1 expression and activity are found in various inflammatory and immune related-diseases, such as hypertension, atherosclerosis, Alzheimer’s disease, inflammatory bowel disease and rheumatoid arthritis. In view of the therapeutic potential of regulating SphK1 and its signal, the current research is aimed at SphK1 inhibitors, such as SphK1 selective inhibitors and dual SphK1/2 inhibitor, and other compounds with inhibitory potency. This review explores the regulatory role of over-expressed SphK1 in inflammatory and immune related-diseases, and investigate the latest progress of SphK1 inhibitors and the improvement of disease or pathological state.

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“…Wang et al [42], Mishra et al [43], Deaton et al [44] and You et al [45] demonstrated that altered expression of SPHK1, WDR13, GIGYF1 and DNMT3A were found to be substantially related to type 2 diabetes mellitus. Altered expression of SPHK1 [46] was easily found in hypertension. Recently, increasing evidence demonstrated that SPHK1 [47] and DNMT3A [48] were altered expression in cognitive diseases.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis of next generation sequencing data for Risk Prediction in Patients with Type 1 diabetes mellitus

Vastrad¹,

Vastrad²

2022

Preprint

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Type 1 diabetes mellitus (T1DM) comprise the most common forms of autoimmune disease. The aim of this investigation was to apply a bioinformatics approach to reveal related pathways or genes involved in the development of T1DM. The next generation sequencing (NGS) dataset GSE182870 was downloaded from the gene expression omnibus (GEO) database. Differentially expressed gene (DEG) analysis was performed using DESeq2. The g:Profiler was utilized to analyze the functional enrichment, gene ontology (GO) and REACTOME pathway of the differentially expressed genes. Protein-protein interaction (PPI) network, modules, miRNA-hub gene regulatory network, and TF-hub gene regulatory network were conducted via comprehensive target prediction and network analyses. Finally, hub genes were validated by using receiver operating characteristic curve analysis. A total of 860 DEGs were screened out from NGS dataset, among which 477 genes were up regulated and 383 genes were down regulated. GO enrichment analysis indicated that up regulated genes were mainly involved in cellular metabolic process, intracellular anatomical structure and catalytic activity, and the down regulated genes were significantly enriched in cellular nitrogen compound biosynthetic process, protein containing complex and heterocyclic compound binding. REACTOME pathway enrichment analysis showed that the up regulated genes were mainly enriched in metabolism of carbohydrates and the down regulated genes were significantly enriched in metabolism of RNA. A PPI network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network were constructed, and hub genes (MAPK14, RHOC, MAD2L1, TAF1, TRAF2, HSP90AA1, TP53, HSP90AB1, UBA52 and RACK1) were identified. This study provides further insights into the underlying pathogenesis of T1DM.

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Targeting Sphingosine Kinase 1 for the Treatment of Pulmonary Arterial Hypertension

Cited by 6 publications

References 98 publications

Transforming Growth Factor β1 Increases Expression of Contractile Genes in Human Pulmonary Arterial Smooth Muscle Cells by Potentiating Sphingosine-1-Phosphate Signaling

Transforming Growth Factor β1 Increases Expression of Contractile Genes in Human Pulmonary Arterial Smooth Muscle Cells by Potentiating Sphingosine-1-Phosphate Signaling

Therapeutic Potential of SphK1 Inhibitors Based on Abnormal Expression of SphK1 in Inflammatory Immune Related-Diseases

Bioinformatics Analysis of next generation sequencing data for Risk Prediction in Patients with Type 1 diabetes mellitus

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