Aldosterone modifies hemostasis via upregulation of the protein-C receptor in human vascular endothelium

Ducros, Elodie; Berthaut, Alexandre; Mirshahi, S.; Faussat, Anne Marie; Soria, Jeannette; Agarwal, M.K.; Mirshahi, Massoud

doi:10.1016/j.bbrc.2008.05.185

Cited by 24 publications

(29 citation statements)

References 30 publications

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“…We had previously shown [16,17] that the mineralocorticoid receptor (MCR)-mediated action of steroid hormones induces neosynthesis of the epithelial sodium channel [15] and also increases the cell volume of capillaries formed by human bone marrow endothelial cells (HBMEC). More recently, we had demonstrated that aldosterone modifies hemostasis via an upregulation of the protein-C receptor in HBMEC [18]. The results presented here demonstrate pleiotropic gene activation by the MCR-mediated action of aldosterone.…”

Section: Introductionmentioning

confidence: 50%

“…As shown here, the underlying molecular events appear to consist of pleiotropic transactivation of genes that regulate capillary hemostasis in situ. Many other reports have variously demonstrated up and down regulation of c-kit ligand (stem cell factor, scf) [36], early growth response protein 1 (egr-1) endothelial protein c receptor [18], cxcr4 [38], cdk-interacting protein 1-p21, [39], protein inhibitor of activated stat2 (pias2) [40], g1/s-specific cyclin d1 (prad1 oncogene [41,42], growth arrest and dna damage inducible protein gadd153 [39], neural cell adhesion molecule l1 precursor (n-cam l1) (cd171 antigen) [43]. More recently, whereas one study has shown transcription regulation of many genes by aldosterone [44], in another report this steroid was shown to have no effect on transactivation [45] in human endothelium.…”

Section: -Procr: (Procr or Epcr) Endothelial Protein C Receptor) (Apmentioning

confidence: 99%

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Pleiotropic Effect of Aldosterone on Human Endothelial Cells In Vitro

Mirshahi¹,

Berthaut²,

Ducros³

et al. 2012

Open Cell Signal J

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Aim: To investigate the effect of aldosterone and its antagonists on cell behavior and gene modulation in human endothelial cells. Methods and Results:Exposure of HBMEC to 100 nM aldosterone reduced the subsequent organization and assembly of cells into capillary-like networks, capillary length and cell multiplication but cell migration to the wound edge was not affected by the agonist. Eplerenone (400 nM) partially reversed the inhibitory effect of the agonist on capillary length, the number of capillary networks, as well as cell multiplication; the antagonist also inhibited the migration of HBMEC in a wound healing assay. Aldactone was more potent than eplerenone in most of the tests, due possibly to the fact that the former derivative is not specific to the MCR but activates other classes of steroid receptors as well. Transcriptional modulation by aldosterone was analyzed using a gene array technique that screened 1800 genes related to cytokines, monokines, growth factors, angiogenic effectors, cell metabolism, growth and malignant transformation. Evidence is provided here for the simultaneous upregulation of 36 mRNAs, and concurrent downregulation of 29 mRNAs, in endothelial cells exposed for 8 h to 100 nM aldosterone.Conclusions: Aldosterone inhibits cell migration, network formation, and cell proliferation in vitro, possibly via a pleiotropic effect on transcription modulation in human endothelial cells.

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Section: Introductionmentioning

confidence: 50%

Section: -Procr: (Procr or Epcr) Endothelial Protein C Receptor) (Apmentioning

confidence: 99%

Pleiotropic Effect of Aldosterone on Human Endothelial Cells In Vitro

Mirshahi¹,

Berthaut²,

Ducros³

et al. 2012

Open Cell Signal J

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“…3 Some in vitro and clinical studies have provided evidence for a link between ALDO and haemostatic disturbances. 1,4 We also showed that ALDO infusion enhanced experimental venous thrombosis in normoglycaemic rats and the mechanisms involved endothelial dysfunction, activation of coagulation and fibrinolysis impairment. 5,6 An EPHESUS trial has shown strong effectiveness of selective mineralocorticoid receptor (MR) antagonist eplerenone (EPL) in the reduction of mortality in patients with heart failure.…”

Section: Introductionmentioning

confidence: 79%

Eplerenone reduces arterial thrombosis in diabetic rats

Zakrzeska

Gromotowicz-Popławska

Szemraj

et al. 2014

J Renin Angiotensin Aldosterone Syst

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Introduction: Clinical studies demonstrated the benefits of eplerenone (EPL) in reduction of cardiovascular events in diabetic patients. Since acute myocardial infarction (AMI) and stroke are related to acute intravascular thrombosis, we postulate that the beneficial effects of EPL may result from its antithrombotic action. Materials and methods: Streptozotocin (STZ)-induced diabetic rats were treated with EPL (100 mg/kg/day) for 10 days. Thrombosis in the carotid artery was stimulated electrically. Results: Thrombosis development was enhanced in STZ-induced diabetic rats as compared to normoglycaemic controls. EPL caused prolongation of the time to artery occlusion, reduction in the incidence of occlusion and decrease in thrombus weight. Changes in the thrombi structure and the inhibition of hypertrophy of the tunica media in the artery wall were also observed. EPL caused reduction in tissue factor, plasminogen activator inhibitor type 1 and interleukin-1β plasma levels. Conclusions: Our study demonstrated the antithrombotic effect of EPL manifested by a decrease in the dynamics of thrombus formation and changes in its structure. The changes in thrombosis process were accompanied by antihaemostatic, profibrinolytic and anti-inflammatory effects. The aldosterone blockade with EPL seems to be an additional pharmacological strategy for the prevention and treatment of thrombotic disorders in diabetes.

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“…OVCAR3 cells (5×10 6 ) were lysed with TRIzol ® reagent (Invitrogen, Carlsbad, CA, USA) and sent to Miltenyi Biotec GmbH in dry ice. The gene array experiment was performed according to the protocol of Ducros et al (16). Expression of IGF-I, IGF-II, IGF-IR, IGF-IIR and IGFBP 1, 2, 3, 4, 6, 10 genes was also studied by gene array.…”

Section: Methodsmentioning

confidence: 99%

Hospicells promote upregulation of the ATP-binding cassette genes by insulin-like growth factor-I via the JAK2/STAT3 signaling pathway in an ovarian cancer cell line

Benabbou

Mirshahi

Cadillon

et al. 2013

International Journal of Oncology

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Interaction between tumor cells and their microenvironment has a crucial role in the development, progression and drug resistance of cancer. Our objective was to confirm the role of Hospicells, which are stromal cells from the cancer microenvironment, in drug resistance and tumor cell growth. We demonstrated that soluble factors secreted by Hospicells activate several genes and upregulate the JAK/STAT signaling pathway in ovarian cancer cell lines. Hospicells express all insulin-like growth factor (IGF) family as detected by gene array, RT-PCR, protein array and immunocytochemistry. While focusing attention on the microenvironment, we considered the role of IGF-I in proliferation and survival of ovarian cancer cells. Indeed, IGF-I is a major regulator of different stages of cancer development. We studied the effect of exogenously added IGF-I on the regulation of ATP-binding cassette (ABC) genes (MDR1, MRP1, MRP2, MRP3, MRP5 and BCRP) in the ovarian cancer cell line OVCAR3 and validated the results obtained using the IGF-IR antagonist picropodophyllin. IGF-I regulates the expression of ABC genes in OVCAR3 cells via the PI3-kinase, MEK and JAK2/STAT3 signaling pathways. The OVCAR3 cell line when co-cultured with Hospicells showed a marked degree of drug resistance. The drug resistance observed could be amplified with exogenous IGF-I. Addition of IGF-IR inhibitor, however, reduced the degree of resistance in these exposed cells. Cells that were treated with anticancer drugs and then exposed to IGF-I showed an increase in drug resistance and, thereby, an increase in cell survival. This observation indicates that drug resistance of OVCAR3 cells increases when there is synergy between OVCAR3 cells and Hospicells and it is amplified when IGF-I was exogenously added. In conclusion, inhibition of IGF-IR and targeting of the JAK2/STAT3 signaling pathway can be a target for ovarian cancer therapy.

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Aldosterone modifies hemostasis via upregulation of the protein-C receptor in human vascular endothelium

Cited by 24 publications

References 30 publications

Pleiotropic Effect of Aldosterone on Human Endothelial Cells In Vitro

Pleiotropic Effect of Aldosterone on Human Endothelial Cells In Vitro

Eplerenone reduces arterial thrombosis in diabetic rats

Hospicells promote upregulation of the ATP-binding cassette genes by insulin-like growth factor-I via the JAK2/STAT3 signaling pathway in an ovarian cancer cell line

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