Enodthelin 1 Is Elevated in Plasma and Explants From Patients Having Uterine Leiomyomas

Wallace, Kedra; Chatman, Krystal; Porter, Justin; Scott, Julie; Johnson, Venessia; Moseley, Janae; LaMarca, Babbette

doi:10.1177/1933719114542018

Cited by 26 publications

(22 citation statements)

References 41 publications

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“…Primer sequences provided by Life technologies (Carlsbad, CA, USA) were used for PPET and b-actin as described previously. 10,28 Placental Explant Culture Freshly harvested placentas from NP and HELLP rats (3 placentas per rat; n ¼ 4 rats/group) were collected and rinsed in cold phosphate-buffered saline, and the myometrium layer was isolated from the decidua to allow excision of the vascular bundle. All collected placentas were within the median placental weight range for each rat.…”

Section: Methodsmentioning

confidence: 99%

Hypertension in an Animal Model of HELLP Syndrome is Associated With Activation of Endothelin 1

et al. 2016

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Women with hypertensive forms of pregnancy such as hemolysis-elevated liver enzymes-low platelet syndrome have increased circulating endothelin 1; however, the relationship between hypertension and endothelin 1 has not been studied. Using an animal model, we sought to determine whether there was an increased activation/dysfunction of endothelin 1, the effect of endothelin 1 receptor-A blockade on hypertension and other manifestations of hemolysis, elevated liver enzymes, and low platelets syndrome. On gestational day 12, timed-pregnant rats were infused with soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEndoglin; 4.7 and 7 µg/kg) via mini-osmotic pumps for 8 days. A subset of rats were treated with receptor-A antagonist (ABT-627, 5mg/kg) for 8 days. Rats with hemolysis-elevated liver enzymes-low platelet syndrome had significantly increased hypertension (P = .0001), circulating endothelin 1 (P = .03), and a significant 3.3- and 7.2-fold increase in preproendothelin messenger RNA (mRNA) expression in the placenta and liver (P = .01 and .04). Urinary protein:creatinine ratio was significantly increased in these animals (P = .0007), and circulating factors from these rats stimulated a significant increase in endothelial cell secretion of endothelin 1 (P = .001) in an in vitro assay. Blockade of the endothelin 1 receptor A significantly decreased hypertension (P = .001), circulating endothelin 1, and interleukin 17 (P = .004 and .003), placental preproendothelin mRNA expression (P = .016), and urinary protein:creatinine ratio (P = .007) in rats with hemolysis-elevated liver enzymes-low platelet syndrome. Blockade of the endothelin 1 receptor A significantly decreased hemolysis (P = .009), liver enzymes (P = .011), and significantly increased platelet levels (P = .03) and decreased circulating CD4+ and CD8+ T lymphocytes (P = .0004 and .0001) in rats infused with sFlt-1 and sEndoglin. These data support the hypothesis that endothelin 1 activation has a critical role in pathophysiology of as hemolysis-elevated liver enzymes-low platelet syndrome.

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Section: Methodsmentioning

confidence: 99%

Hypertension in an Animal Model of HELLP Syndrome is Associated With Activation of Endothelin 1

et al. 2016

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“…Protein blood biomarkers such as carcinoembryonic antigen (CEA), cancer antigen 19–9 (CA19-9) and prostate specific antigen (PSA) used in this study, have been widely studied for many decades and are used in mainstream clinical disease management [ 20 – 24 ]. Endothelin-1, cancer antigen 125 (CA125) and cancer antigen 15–3 (CA15-3) have been studied in uterine fibroids [ 25 – 27 ]. Circulating nucleic acid biomarkers are also being explored as potential non-invasive disease detection agents.…”

Section: Introductionmentioning

confidence: 99%

Tumor characterization by ultrasound-release of multiple protein and microRNA biomarkers, preclinical and clinical evidence

et al. 2018

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We have previously shown that low frequency ultrasound can release biomarkers from cells into the murine circulation enabling an amplification and localization of the released biomarker that could be used as a blood-based method to detect cancer earlier and monitor therapy. In this study, we further demonstrate that this technique could be used for characterization of tumors and/or identification of cellular masses of unknown origin due to the release of multiple protein and nucleic acid biomarkers in cells in culture, mice and patients. We sonicated colon (LS174T) and prostate (LNCaP) cancer cell lines in culture at a low frequency of 1 MHz and show that there were several-fold changes in multiple protein and microRNA (miRNA) abundance with treatment at various intensities and time. This release was dependent on the duration and intensity of the sonication for both cell lines. Significant increased release in biomarkers was also observed following tumor sonication in living mice bearing subcutaneous LS174T cell line xenografts (for proteins and nucleic acids) and in an experimental LS174T liver tumor model (for proteins only). Finally, we demonstrated this methodology of multiple biomarker release in patients undergoing ablation of uterine fibroids using MR guided high intensity focused ultrasound. Two protein biomarkers significantly increased in the plasma after the ultrasound treatment in 21 samples tested. This proof that ultrasound-amplification method works in soft tissue tumor models together with biomarker multiplexing, could allow for an effective non-invasive method for identification, characterization and localization of incidental lesions, cancer and other disease. Pre-treatment quantification of the biomarkers, allows for individualization of quantitative comparisons. This individualization of normal marker levels in this method allows for specificity of the biomarker-increase to each patient, tumor or organ being studied.

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“…The vasoconstrictive peptide ET-1 is induced by hypoxia in fibroids, via the ET A receptor which is overexpressed in fibroids, and induces proliferation of leiomyoma cells [2,15,26]. To determine if hypoxia stimulated ET-1 release from SMCs via the ET A receptor, we used an ET A receptor antagonist in the cell culture medium as a reduction in ET-1 secretion from SMCs would indicate that ET-1 secretion is being regulated through the ET A receptor [27,28].…”

Section: Discussionmentioning

confidence: 99%

“…SMCs were seeded at 25,000 cells/well in 2.5 ml of media and incubated under hypoxic (1% O 2 ) or normoxic (6% O 2 ) conditions in a humidified atmosphere at 37°C for a period of 24 h utilizing a ProOx P110 oxygen-controlled hypoxia chamber (BioSpherix) as previously described [15]. To determine the role of the endothelin activation, SMCs were also seeded at 25,000 cells/well in 2.5 ml of media with 1.0 μM ABT-627 (ET A antagonist used to determine if ET-1 secretion is due to the stimulation of this receptor) and incubated under hypoxic or normoxic conditions for 24 h. At the end of the 24-h incubation, cell culture media was collected, and the cells were harvested for cell counts and lysed for protein analysis.…”

Section: Experimental Methodsmentioning

confidence: 99%

“…CYR61 has been reported to decrease smooth muscle cell (SMC) vasoconstriction, which is one of the functions of ET-1, suggesting that the decrease in CYR61 reported in women with uterine fibroids might coincide with the increase in ET-1 [12]. ET-1 has been suggested to have a role in the development of fibroids through both activation of the endothelin A (ET A ) receptor and chronic periods of hypoxia [13–15]. Similar to CYR61, ET-1 and hypoxia both have roles in angiogenesis and cell proliferation [16–18].…”

Section: Introductionmentioning

confidence: 99%

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Novel treatment avenues for uterine leiomyoma: a new implication for endothelin?

et al. 2018

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Cysteine-rich angiogenic inducer 61 (CYR61), an angiogenic factor whose expression is decreased in fibroids. The aim of the present study was to determine if CYR61 secretion in smooth muscle cells (SMCs) is regulated by hypoxia and through the endothelin A (ETA) receptor. SMCs from fibroids (fSMC) and the adjacent myometrium smooth muscle cells (mSMCs) were extracted from ten women undergoing hysterectomy for uterine fibroids and cultured with or without 1.0 μM of an ETA receptor antagonist for 24 h under either normal or hypoxic oxygen conditions. Cellular secretion of endothelin-1 (ET-1) and CYR61 were measured via enzyme linked immunosorbent assay in the cell culture media. SMCs were collected to determine cell proliferation and CYR61 protein expression via Western blot. ET-1 secretion was significantly increased in fSMC and was decreased with blockade of the ETA receptor under both normoxia (P=0.0004) and hypoxia (P=0.008). CYR61 expression was decreased in fSMCs and significantly increased with blockade of the ETA receptor under hypoxia (P=0.04). Cell proliferation decreased with ETA blockade under normoxia (P=0.0001) and hypoxia (P=0.001). These results suggest that suppression of CYR61 secretion in fSMC is regulated by the ET-1 and that blockade with ETA could be considered for a future treatment option.

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Enodthelin 1 Is Elevated in Plasma and Explants From Patients Having Uterine Leiomyomas

Cited by 26 publications

References 41 publications

Hypertension in an Animal Model of HELLP Syndrome is Associated With Activation of Endothelin 1

Hypertension in an Animal Model of HELLP Syndrome is Associated With Activation of Endothelin 1

Tumor characterization by ultrasound-release of multiple protein and microRNA biomarkers, preclinical and clinical evidence

Novel treatment avenues for uterine leiomyoma: a new implication for endothelin?

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