Downregulation of endothelial nitric oxide synthase (eNOS) and endothelin1 (ET1) in a co-culture system with human stimulated X-linked CGD neutrophils.

Phagocytes in patients with chronic granulomatous disease (CGD) do not generate reactive oxidative species (ROS), whereas nitric oxide (NO) production is increased in response to the calcium ionophore A23187 in CGD phagocytes compared with healthy phagocytes. Recently, patients with X-linked CGD (X-CGD) have been reported to show higher flow-mediated dilation, suggesting that endothelial cell function is affected by NO production from phagocytes. We studied NOS3 and EDN1 mRNA and protein expression in human umbilical vein endothelial cells (HUVECs) in a co-culture system with neutrophils from X-CGD patients. HUVECs were co-cultured for 30 minutes with human neutrophils from X-CGD or healthy participants in response to A23187 without cell-to-cell contact. The expression of NOS3 and EDN1 mRNA in HUVECs was quantified by real-time polymerase chain reaction. Moreover, we demonstrated the protein expression of eNOS, ET-1, and NFκB p65, including phosphorylation at Ser1177 of eNOS and Ser536 of NFκB p65. Neutrophils from X-CGD patients showed significantly higher NO and lower H2O2 production in response to A23187 than healthy neutrophils in vitro.
Compared with healthy neutrophils, X-CGD neutrophils under A23187 stimulation exhibited significantly increased NO and decreased H2O2, and promoted downregulated NOS3 and EDN1 expression in HUVECs. The total expression and phosphorylation at Ser1177 of eNOS and ET-1 expression were significantly decreased in HUVECs co-cultures with stimulated X-CGD neutrophils. Also, phosphorylation at Ser536 of NFκB p65 were significantly decreased. In conclusions, eNOS and ET-1 significantly down-regulated in co-culture with stimulated X-CGD neutrophils through their excessive NO and the lack of ROS production. These findings suggest that ROS generated from neutrophils may mediate arterial tone affecting eNOS and ET-1 expression via their NO and ROS production.

<em>Endothelin</em>-<em>1</em> (<em>ET</em>-<em>1</em>) Promotes a Proinflammatory Microglia Phenotype in Diabetic Conditions.

Diabetes increases the risk and severity of cognitive impairment, especially after ischemic stroke. It is also known that the activation of ET system is associated with cognitive impairment and microglia around periinfarct area produce ET-1. However, little is known about the effect of ET-1 on microglial polarization, especially under diabetic conditions. We hypothesized that a) ET-1 activates microglia to proinflammatory M-1 like phenotype, and b) Hypoxia/LPS activates the microglial ET system and promotes microglial activation towards M-1 phenotype in diabetic conditions.
Microglial cells (C8B4) cultured under normal glucose (25mM) and diabetes-mimicking high glucose (50mM) conditions for 48 hours were stimulated with ET-1, cobalt chloride (200µM) or lipopolysaccharide (100ng/ml) for 24 hours. PPET-1, ET receptor subtypes and M1/M2 marker genes mRNA expression measured by RT-PCR. Secreted ET-1 was measured by ELISA. High dose of ET-1 (1µM), increases the mRNA levels of ET receptors and activates the microglia towards M1 phenotype. Hypoxia or LPS activates the ET system in microglial cells and shifts the microglia towards M1 phenotype in diabetic conditions. These in vitro observations warrant further investigation into the role of ET-1-mediated activation of proinflammatory microglia in post-stroke cognitive impairment in diabetes.

Evaluation of plasma and tissue expression levels of <em>Endothelins</em> (<em>ET</em>-<em>1</em>, Big <em>ET</em>-<em>1</em>) and VEGF in lobular neoplasia of the breast.

The endothelin system is involved in the evolution of multiple malignancies, participating in cancer cell proliferation, tumor invasion and angiogenesis. Our purpose was to simultaneously assess endothelin expression in the systemic circulation of patients with lobular neoplasia (LN) of the breast and to investigate its correlation with vascular endothelial growth factor (VEGF) specimen expression levels as well as clinicopathologic findings.This was a retrospective analysis of prospectively collected data regarding 60 women examined in a single breast unit. Thirty of these women underwent stereotactic biopsy and were diagnosed with LN and the remaining 30 were healthy controls. Circulating levels of endothelin (ET)-1 and Big ET-1 were measured using ELISA, while tissue expression of ET-1 and VEGF in biopsy specimens were assessed using qualitative immunohistochemical staining.
The plasma levels of Big ET-1 were significantly increased in patients with LN compared to healthy controls. There was no significant difference in the plasma levels of ET-1 between the patient groups. In patients with LN, plasma expression of ET-1 and Big ET-1 did not correlate with ET-1 or VEGF tissue expression status, neither existed a relationship between tissue expressions of ET-1 and VEGF.Our results imply that Big ET-1 is a potential biomarker for LN. Further investigation of the endothelin system role in LN seems a promising research field.

The rise of circulatory <em>endothelin</em> (<em>ET</em>)-<em>1</em> and <em>endothelin</em> receptors (<em>ET</em>A, <em>ET</em>B) expression in kidney of obese wistar rat.

BACKGROUND
Endothelin (ET)-1, a circulatory protein, and its receptors (ETA and ETB) in various organs were reported to play a pivotal role in many diseases, including obesity. However, the changes of ETA and ETB expression in ventricle and kidney in obesity was less reported. The study is designed to observe the level of circulatory ET-1 and expression of ETA/ETB in ventricle and kidney of obese, as compared to non-obese, Wistar rats.

METHODS

Groups of obese 14 and 34 weeks Wistar rats were compared to non-obese controls at similar ages. The obesity status was achieved by feeding the with high calories protein diet CP 551 + milk powder, while the control group was fed with a standard calorie protein AD II diet. The concentration of circulatory ET-1, ETA and ETB of ventricle and kidney were measured by Enzyme Linked Immunosorbent Assay (ELISA) technique after the termination of both groups at 14th and 24th weeks.

RESULTS

The level of circulatory ET-1, expression of ETA and ETB in kidney, and LDL of obese rats were significantly higher than control rats (T-Test, P<0.05) in the elder groups, while no differences of the ETA and ETB were found in the ventricle. No differences of the levels of circulatory ET-1, ETA and ETB expression were found between obese and control groups of younger rats (P>0.05). HDL levels were under normal value for both groups.

CONCLUSION

Obesity in elder obese rats leads to dysregulation of kidney vessels through activity of ET-1 and ETA/ETB.

Endothelin 1 (ET-1) Antibody

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Atorvastatin Prevents Myocardial Fibrosis in Spontaneous Hypertension via Interleukin-6 (IL-6)/Signal Transducer and Activator of Transcription 3 (STAT3)/<em>Endothelin</em>-<em>1</em> (<em>ET</em>-<em>1</em>) Pathway.

BACKGROUND Hypertension is a leading global disease, and myocardial fibrosis is an important adverse effect of hypertension, seriously threatening human health. The IL-6/STAT3 pathway and endothelin-1 (ET-1) were previously suggested to play a part in myocardial fibrosis. MATERIAL AND METHODS To investigate the role of Atorvastatin (Ato) in spontaneous hypertension, systolic blood pressure (SBP) and left ventricular mass index (LVMI) were measured, and Masson trichrome staining was performed.
Furthermore, the relative protein levels of the IL-6/STAT3/ET-1 pathway were tested. RESULTS Ato prevented myocardial fibrosis in spontaneous hypertension rats, especially at the dosage of 50 mg/kg/d. The IL-6/STAT3 pathway was observed to be suppressed by Ato, and ET-1 level in myocardial tissues was also downregulated by Ato. The phosphorylation status of STAT3 was tested after Ato treatment, showing that Ato mainly stimulated the tyr-705 phosphorylation of STAT3. CONCLUSIONS Results of this study may help promote myocardial fibrosis therapy and provide insights into the IL-6/STAT3/ET-1-mediated mechanism in Ato-induced myocardial fibrosis inhibition.

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