Inhibition of JAK/STAT signaling pathway prevents high-glucose-induced increase in endothelin-1 synthesis in human endothelial cells

Manea, Simona-Adriana; Manea, Adrian; Heltianu, Constantina

doi:10.1007/s00441-010-0936-1

Cited by 34 publications

(34 citation statements)

References 26 publications

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“…34 Our study supports the hypothesis that the pathogenesis of thrombosis in MPN may result from an endothelial progenitor cell dysfunction, as well. In fact, we show that the JAK2 mutation in endothelial cells abnormally activates the JAK/STAT pathway, which is an important regulator of the response of endothelial cells to injury 35,36 and increases their proficiency to adhere to normal mononuclear cells. Interestingly, 2 of the 3 patients exhibiting clonal and mutated E-CFCs had thrombosis in the splanchnic veins (1 portal thrombosis and 1 BCS), whereas a third patient presenting with massive bleeding from gastric varices had severe portal hypertension, albeit in the absence of evident previous portal or suprahepatic vein thrombosis.…”

Section: Discussionmentioning

confidence: 82%

Endothelial progenitor cells are clonal and exhibit the JAK2V617F mutation in a subset of thrombotic patients with Ph-negative myeloproliferative neoplasms

Teofili¹,

Martini

Iachininoto³

et al. 2011

Blood

108

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In this study we investigated whether neoplastic transformation occurring in Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs) could involve also the endothelial cell compartment. We evaluated the level of endothelial colony-forming cells (E-CFCs) in 42 patients (15 with polycythemia vera, 12 with essential thrombocythemia, and 15 with primary myelofibrosis). All patients had 1 molecular abnormality (JAK2 V617F or MPL W515K mutations, SOCS gene hypermethylation, clonal pattern of growth) detectable in their granulocytes. The growth of colonies was obtained in 22 patients and, among them, patients with primary myelofibrosis exhibited the highest level of E-CFCs. We found that E-CFCs exhibited no molecular abnormalities in12 patients, had SOCS gene hypermethylation, were polyclonal at human androgen receptor analysis in 5 patients, and resulted in JAK2 V617F mutated and clonal in 5 additional patients, all experiencing thrombotic complications. On the whole, patients with altered E-CFCs required antiproliferative therapy more frequently than patients with normal E-CFCs. Moreover JAK2 V617F -positive E-CFCs showed signal transducer and activator of transcription 5 and 3 phosphorylation rates higher than E-CFCs isolated from healthy persons and patients with MPN without molecular abnormalities. Finally, JAK2 V617F -positive E-CFCs exhibited a high proficiency to adhere to normal mononuclear cells. This study highlights a novel mechanism underlying the thrombophilia observed in MPN. (Blood. 2011;117(9):2700-2707)

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Section: Discussionmentioning

confidence: 82%

Endothelial progenitor cells are clonal and exhibit the JAK2V617F mutation in a subset of thrombotic patients with Ph-negative myeloproliferative neoplasms

Teofili¹,

Martini

Iachininoto³

et al. 2011

Blood

108

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“…[15,27] In accordance to this, we have demonstrated previously that the pro-inflammatory signaling pathway, Jak/STAT, mediates the up-regulation of ET-1 biosynthesis in human EC exposed to high glucose concentration. [16] Compelling evidence highlights that various members of the C/EBP transcription factor family play a major role in the onset and development of cardiovascular diseases. It has been demonstrated that inhibition of C/EBP transcriptional activity by decoy oligodeoxynucleotide reduces the restenosis after angioplasty in hypercholesterolemic rabbits, a process that may be partially mediated by the reduction in ET-1 expression.…”

Section: Discussionmentioning

confidence: 99%

“…To ascertain the previous findings [16,33] that high glucose induces ET-1 level and to validate the experimental model, dosedependent experiments were done in EC exposed to increasing concentrations of glucose. The results proved high glucose augments ET-1 biosynthesis and regulates its expression at multiple levels such gene transcription, mRNA expression, intracellular processing and peptide secretion into the culture medium in both EC line (EAhy926) and in primary cultures of human aortic EC.…”

Section: Discussionmentioning

confidence: 99%

“…[13] Multiple mitogenic signaling pathways [(e.g., mitogen-activated protein kinases (MAPK), Janus kinase (Jak)] and pro-inflammatory transcription factors such as nuclear factor kB (NF-kB), activator protein 1 (AP-1), and members of the signal transducer and activator of transcription (STAT) family have been implicated in the regulation of ET-1 expression. [14][15][16] However, the precise molecular pathways responsible for increased ET-1 level in diabetes are not totally deciphered.…”

Section: Introductionmentioning

confidence: 99%

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High glucose-induced increased expression of endothelin-1 in human endothelial cells is mediated by activated CCAAT/enhancer-binding proteins

Manea¹,

Todirita²,

Heltianu³

et al. 2013

European Heart Journal

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High glucose-induced endothelial dysfunction is partially mediated by the down-stream pathophysiological effects triggered by increased expression of endothelin-1 (ET-1). The molecular control mechanisms of ET-1 synthesis are yet to be discovered. Members of the CCAAT/enhancer-binding proteins (C/EBP) family are important regulators of key metabolic processes, cellular differentiation and proinflammatory genes. In this study, we aimed at elucidating the role of C/EBP in mediating the high glucose effect on ET-1 expression in human endothelial cells (EC). Human umbilical vein cells (EAhy926) and primary cultures of human aortic EC were exposed to high levels of glucose (16.5-25 mM). Real-time PCR, Western blot, enzyme-linked immunosorbent assay, ET-1 promoter-luciferase reporter analysis, and chromatin immunoprecipitation assays were employed to investigate ET-1 regulation. High glucose activated C/EBPa, C/EBPb, and C/EBPd in a dosedependent manner. It also promoted significant increases in ET-1 gene and peptide expression. Chemical inhibition of JNK, p38MAPK and ERK1/2 diminished significantly the high glucose-induced nuclear translocation of C/EBP and ET-1 expression. Silencing of C/EBPa, C/EBPb or C/EBPd greatly reduced the high glucose-induced upregulation of ET-1 mRNA, pre-pro-ET-1, and ET-1 secretion. The expression of various C/EBP isoforms was selectively downregulated by siRNA-mediated gene silencing. In silico analysis indicated the existence of typical C/EBP elements within human ET-1 gene promoter. Transient overexpression of C/EBPa, C/EBPb or C/EBPd upregulated the luciferase level controlled by the ET-1 gene promoter. The direct interaction of C/EBPa, C/EBPb or C/EBPd proteins with the ET-1 promoter in high glucose-exposed EC was confirmed by chromatin immunoprecipitation assay. High glucose-induced ET-1 expression is mediated through multiple mechanisms. We present evidence that members of the C/EBP proinflammatory transcription factors are important regulators of ET-1 in high glucose-exposed human endothelial cells. High glucose-induced activation of C/EBP-related signaling pathways may induce excessive ET-1 synthesis, thus promoting vasoconstriction and dysfunction of the vascular wall cells in diabetes.

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“…Previous studies demonstrated that the combined treatment of anti-placental growth factor (PLGF) and vascular endothelial growth factor A (VEGF-A) could reduce ocular hemangiomas growth and choroidal neovascularization [28,29]. The activation of the SOCS/JAK/STAT signaling pathway is an essential pathogenic mechanism leading to endothelial cell dysfunction [30][31][32]. AG490 is a common inhibitor of JAK2 kinase and inhibits the expression of SOCS1 [33].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the JAK2/STAT3/SOSC1 Signaling Pathway Improves Secretion Function of Vascular Endothelial Cells in a Rat Model of Pregnancy-Induced Hypertension

Luo

et al. 2016

Cell Physiol Biochem

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Background/Aims: The present study aimed to investigate the effects of the JAK2/STAT3/SOSC1 signaling pathway on the secretion function of vascular endothelial cells (VECs) in a rat model of pregnancy-induced hypertension (PIH). Methods: A PIH rat model was established. Forty-eight pregnant Sprague-Dawley female rats were selected and assigned into four groups: the normal group (normal non-pregnant rats), the non-PIH group (pregnant rats without PIH), the PIH group (pregnant rats with PIH) and the AG490 group (pregnant rats with PIH treated with AG490). Systolic blood pressure (SBP) and urinary protein (UP) were measured. The expressions of JAK2/STAT3/SOSC1 signaling pathway-related proteins in placenta tissues were detect by Western blotting. Radioimmunoassay was applied to detect serum levels of nitric oxide (NO), super oxide dismutase (SOD), placental growth factor (PGF), thromboxane B2 (TXB2) and endothelin (ET). Enzyme-linked immunosorbent assay (ELISA) was used to determine serum levels of interleukin-6 (IL-6), interleukin-10 (IL-10) and tumor necrosis factor-α (TNF-α). Results: Compared with the normal and non-PIH groups, the PIH and AG490 groups had higher SBP and UP levels at 17^th and 25^th day of pregnancy. The expressions of p/t-JAK2, p/t-STAT3 and SOSC1 in the PIH and AG490 groups were higher than those in the non-PIH group, while the expressions of p/t-JAK2, p/t-STAT3 and SOSC1 in the AG490 group were lower than those in the PIH group. Compared with the non-PIH group, serum levels of ET, TXB2, IL-6 and TNF-α were increased in the PIH and AG490 groups, while serum levels of NO, SOD, 6-keto-PGF1a and IL-10 levels were reduced. Furthermore, the AG490 had lower serum levels of ET, TXB2, IL-6 and TNF-α and higher serum levels of NO, SOD, 6-keto-PGF1a and IL-10 than those in the PIH group. Conclusion: Our study provides evidence that inhibition of the JAK2/STAT3/SOSC1 signaling pathway could improve the secretion function of VECs in PIH rats.

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Inhibition of JAK/STAT signaling pathway prevents high-glucose-induced increase in endothelin-1 synthesis in human endothelial cells

Cited by 34 publications

References 26 publications

Endothelial progenitor cells are clonal and exhibit the JAK2V617F mutation in a subset of thrombotic patients with Ph-negative myeloproliferative neoplasms

Endothelial progenitor cells are clonal and exhibit the JAK2V617F mutation in a subset of thrombotic patients with Ph-negative myeloproliferative neoplasms

High glucose-induced increased expression of endothelin-1 in human endothelial cells is mediated by activated CCAAT/enhancer-binding proteins

Inhibition of the JAK2/STAT3/SOSC1 Signaling Pathway Improves Secretion Function of Vascular Endothelial Cells in a Rat Model of Pregnancy-Induced Hypertension

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