Endothelin-1 Concentrations Research Articles

Aqueous Cichorium intybus L. seed extract may protect against acute palmitate-induced impairment in cultured human umbilical vein endothelial cells by adjusting the Akt/eNOS pathway, ROS: NO ratio and ET-1 concentration.

Endothelial dysfunction, which is a vascular response to oxidative stress and inflammation, involves a cascade of downstream events that lead to decreased synthesis of insulin-mediated vasodilator nitric oxide (NO) and increased production of vasoconstrictor protein endothelin-1 (ET-1). NO, and ET-1 production by endothelial cells is regulated by phosphatidylinositol 3-kinase (PI3K)-Akt-eNOS axis and mitogen-activated protein kinase (MAPK) axis of the insulin signaling pathway, respectively. After treating the human umbilical vein endothelial cells (HUVECs) with either palmitate complexed with bovine serum albumin (BSA) (abbreviated as PA) or the aqueous Cichorium intybus L. (chicory) seed extract (chicory seed extract, abbreviated as CSE) alone, and simultaneously together (PA + CSE), for 3, 12, and 24h, we evaluated the capacity of CSE to reestablish the PA-induced imbalance between PI3K/Akt/eNOS and MAPK signaling pathways. The level of oxidative stress was determined by fluorimeter. Insulin-induced levels of NO and ET-1 were measured by Griess and ELISA methods, respectively. Western blotting was used to determine the extent of Akt and eNOS phosphorylation. Contrary to PA that caused an increase in the reactive oxygen species (ROS) levels and attenuated NO production, CSE readjusted the NO/ROS ratio within 12h. CSE improved the metabolic arm of the insulin signaling pathway by up-regulating the insulin-stimulated phospho-eNOS Ser1177/total eNOS and phospho-Akt Thr308/total Akt ratios and decreased ET-1 levels. CSE ameliorated the PA-induced endothelial dysfunction not only by its anti-ROS property but also by selectively enhancing the protective arm and diminishing the injurious arm of insulin signaling pathways.

Quercetin attenuates reduced uterine perfusion pressure -induced hypertension in pregnant rats through regulation of endothelin-1 and endothelin-1 type A receptor

BackgroundQuercetin was reported to be crucial for a broad range of activities, including attenuating inflammation, platelet aggregation, capillary permeability, and lipid peroxidation. However, the effect of quercetin in hypertension during pregnancy, was not fully understood.MethodsThe model of hypertension in pregnancy was established in rats by reduced uterine perfusion pressure (RUPP). Quercetin was administrated by gavage. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured using the CODA 6 BP system. Plasma concentrations of Endothelin-1 (ET-1), soluble fms-like tyrosine kinase-1 (sFlt-1), and vascular endothelial growth factor (VEGF) were detected using enzyme-linked immunosorbent assay kits. The mRNA and protein levels of ET-1 and endothelin-1 type A receptor (ETAR) were determined by RT-PCR and Western blotting. The ETAR antagonist BQ-123 was performed by osmotic minipumps.ResultsIn RUPP induced rats, quercetin treatment decreased SBP and DBP, fetal resorptions percentage, plasma ET-1 and sFlt-1 concentrations, ET-1 and ETAR levels, but increased fetal body weight and VEGF expression. BQ-123 administration attenuated SBP and DBP, suppressed fatal resorptions percentage, and increased fetal body weight of RUPP rats.ConclusionQuercetin attenuates RUPP induced hypertension in pregnant rats through the regulation of ET-1 and ETAR.

Estimation of efficiency of shock wave therapy in patients with chronic nonbacterial prostatitis / chronic pelvic pain syndrome

Estimation of efficiency of shock wave therapy in patients with chronic nonbacterial prostatitis / chronic pelvic pain syndrome

Podocytes-The Most Vulnerable Renal Cells in Preeclampsia.

Preeclampsia (PE) is a disorder that affects 3–5% of normal pregnancies. It was believed for a long time that the kidney, similarly to all vessels in the whole system, only sustained endothelial damage. The current knowledge gives rise to a presumption that the main role in the development of proteinuria is played by damage to the podocytes and their slit diaphragm. The podocyte damage mechanism in preeclampsia is connected to free VEGF and nitric oxide (NO) deficiency, and an increased concentration of endothelin-1 and oxidative stress. From national cohort studies, we know that women who had preeclampsia in at least one pregnancy carried five times the risk of developing end-stage renal disease (ESRD) when compared to women with physiological pregnancies. The focal segmental glomerulosclerosis (FSGS) is the dominant histopathological lesion in women with a history of PE. The kidney’s podocytes are not subject to replacement or proliferation. Podocyte depletion exceeding 20% resulted in FSGS, which is a reason for the later development of ESRD. In this review, we present the mechanism of kidney (especially podocytes) injury in preeclampsia. We try to explain how this damage affects further changes in the morphology and function of the kidneys after pregnancy.

Angiotensin I-Converting Enzyme (ACE) Inhibitory and Antioxidant Activity of Umami Peptides after In Vitro Gastrointestinal Digestion

Umami peptides can help reduce the salt content in foods while still maintaining a savory taste. Few studies have reported the bioactivity of umami peptides after consumption. We studied the bioactivities of 12 umami peptides after gastrointestinal digestion. Three umami peptides exhibited angiotensin I-converting enzyme (ACE) inhibitory and antioxidant activity after digestion. Six novel peptides were identified from digestion solutions of the peptides by HPLC-MS/MS. Among them, CC, CCNK, and HCHT had both ACE inhibitory activity (IC50 values were 9.81, 9.00, and 114.99 μM, respectively) and antioxidant activity (strong 1,1-Diphenyl-2-pycryl-hydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) free radical scavenging activities). AHSVRF had strong ACE inhibitory activity. These peptides increased the nitric oxide concentration and decreased the content of endothelin-1 in a medium of human umbilical vein endothelial cells in a dose-dependent manner. Experiments with damaged HepG2 cells showed that peptides CC, CCNK, and HCHT had antioxidant activity through their cytoprotective effects and by reducing the reactive oxygen species content. The results indicated that umami peptides may provide many health benefits after consumption.

Iron overload is related to elevated blood glucose levels in obese children and aggravates high glucose-induced endothelial cell dysfunction in vitro

IntroductionThis study was performed to investigate the role of iron overload in the early stage of hyperglycemia-induced vascular functional impairment.Research design and methodsA total of 196 obese children were enrolled,...

Acute effects of sitagliptin on progenitor cells and soluble mediators in newly diagnosed type 2 diabetes.

Studies have confirmed that endothelial progenitor cells (EPCs) are involved in diabetic complications. The present study assessed the action of the dipeptidyl peptidase-4 inhibitor sitagliptin on EPCs in newly diagnosed type 2 diabetes patients. 60 newly-diagnosed type 2 diabetes patients were randomly divided into three treatment groups: sitagliptin (n = 20), metformin (n = 20), and combination sitagliptin and metformin (n = 20). Patients were treated once daily for 3 days. Before and after each treatment, the number of EPCs and concentration of soluble mediators (glucagon-like peptide 1 (GLP-1), nitric oxide (NO), endothelin-1 (ET-1), and stromal cell-derived factor-1α (SDF-1α)) were determined. The number of CD34+KDR+ and CD34+CD133+KDR+ EPCs and concentration of GLP-1, NO, and SDF-1α in sitagliptin and combination groups were both increased (both p<0.05) but to a greater extent in the combination group (p<0.05). Pearson correlation analysis and multiple linear regression analyses showed that the change in EPC numbers correlated with changes in peripheral GLP-1, NO, and SDF-1α levels (p<0.05). Sitagliptin is able to directly increase the number of peripheral blood EPCs. This direct effect is to be important for lowering vascular risk in early diabetes before macrovascular complications appear.

The dynamics of endothelial dysfunction markers among patients with pulmonary hypertension on the background of chronic obstructive pulmonary disease under the influence of treatment

The objective of the research - to determine the dynamics of endothelial dysfunction markers among patients with pulmonary hypertension on the background of chronic obstructive pulmonary disease under the influence of treatment.Material and methods. The results of the study are based on data from a comprehensive survey of 170 patients with chronic obstructive pulmonary disease (COPD) aged from 40 to 65 years, 123 of which had pulmonary hypertension and 47 ones had no pulmonary hypertension. Also 31 almost healthy people were examined on an outpatient basis. Patients with pulmonary hypertension on a background of COPD were divided into two subgroups of observations depending on the treatment. The first subgroup was used as the background therapy and the second subgroup - background therapy with the roflumilast. Markers of endothelial function were determined during screening and after 12 months of follow-up.Results. The median level of endothelin-1 in the group of patients with pulmonary hypertension on the background of COPD was 3.17 [2.19 ; 4.14] fmol/ ml and was significantly higher, both against the value of 1.78 [1.25 ; 2.18] fmol/ml in the group of COPD patients without pulmonary hypertension (p &lt; 0.05), and 10.2 times higher than versus the level of 0.31 [0.19 ; 0.36] fmol/ml in the group of healthy individuals (p&lt;0.05). The amount of nitrogen oxide metabolites (NO2+NO3) was significantly lower (by 15.8 %) in the group of patients with pulmonary hypertension on the background of COPD versus the value of 22.00 [21.00 ; 23,00] mmol/l in the group of COPD patients without pulmonary hypertension, and is 37 % lower than in the group of healthy individuals, where the level of this indicator was 26,00 [25,00 ; 28,00] mmol/l (p&lt;0.05). Then a correlation analysis was performed. Significant relationships were determined between the following indicators: duration of COPD and NO3 level (R = -0.29, p = 0.001); duration of COPD and NO2+ NO3 level (R - 0.26, p = 0.003); mean pulmonary artery pressure and endothelial-1 level (R = +0.70, p = 0.001); mean pulmonary artery pressure and NO2 level (R = -0.59, p = 0.001); mean pulmonary artery pressure and NO2+ NO3 (R = -0.50, p = 0.001). The level of endothelin-1 and nitrogen oxide metabolites in the blood plasma of patients was comparable between the first and second subgroups of observation during screening (p &gt; 0.05). After 12 months, there was a statistically significant decrease of Δ1% = -57.53 % endothelin-1 to 1.87 [1.44; 2.36] fmol/ml in the first subgroup and Δ2% = -82.34 % to 1.62 [1.37; 1.92] fmol/ml in the second subgroup. After 12 months of therapy in both subgroups, the level of total nitrogen oxide metabolites in blood plasma significantly increased Δ1% = 10.00 % to 21.00 [18.00 ; 23.00] mmol/l in the basic therapy subgroup, and Δ2% = 19.05 % to 24.00 [22.00; 26.00] mmol/l in the roflumilast subgroup, (p &lt; 0.05). A statistically significant difference in endothelin-1 levels and the amount of nitrogen oxide metabolites between subgroups was determined after 12 months of treatment.Conclusions. Among patients with COPD, endothelial dysfunction occurs, characterized by an increase in the concentration of endothelin-1 and a decrease in nitrogen oxide metabolites in the blood plasma. An increase in the level of endothelin-1 in blood plasma has a direct correlation with the value of the mean pulmonary artery pressure. Background therapy among patients with pulmonary hypertension on the background of COPD improves the state of endothelial function, with increased nitrogen oxide metabolites in the blood plasma. When added to background therapy, roflumilast significantly reduced the concentration of endothelin-1 in blood plasma.

First trimester inflammatory mediators in women with chronic hypertension.

Chronic hypertension complicates 1%-2% of pregnancies and is one of the most significant risk factors for the development of preeclampsia. Inflammatory mediators, such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), vascular cell adhesion molecule (VCAM) and endothelin have been implicated in the endothelial dysfunction that is pathognomonic of preeclampsia and may serve as useful first trimester biomarkers for the prediction of preeclampsia. The objectives of this study are: first, to investigate differences in serum levels of IL-6, TNF-α, VCAM and endothelin at 11+0 to 13+6 weeks' gestation in women with chronic hypertension who developed superimposed preeclampsia with those who did not and normotensive controls and, second, to evaluate the performance of these biomarkers in the prediction of preeclampsia. The study population was comprised of 650 women with chronic hypertension, including 202 who developed superimposed preeclampsia and 448 who did not, and 142 normotensive controls matched to the chronic hypertension group for storage time and racial origin. Serum concentrations of IL-6, TNF-α, VCAM and endothelin were measured and the values were converted into multiples of the expected median using multivariate regression analysis in the control group. The multiples of the median values of the biomarkers between the two groups of women with chronic hypertension and the controls were compared, and the receiver operating characteristic curve (ROC) was used to assess the performance of these variables for the prediction of preeclampsia. In women with chronic hypertension, compared with the normotensive controls, there was a significantly higher first trimester median concentration of endothelin but not of VCAM, IL-6 or TNF-α. Within the cohort of women with chronic hypertension, those who developed superimposed preeclampsia, compared with those who did not, had higher first trimester serum concentration of VCAM but not of endothelin, IL-6 or TNF-α. However, serum VCAM provided a poor prediction of superimposed preeclampsia (area under the ROC curve 0.537, 95% CI 0.487-0.587). Women with chronic hypertension have increased serum endothelin in the first trimester of pregnancy and those who develop superimposed preeclampsia have higher levels of VCAM. None of the inflammatory mediators performed well in the first trimester in the prediction of preeclampsia.

THE CLINICAL SIGNIFICANCE OF MARKERS OF ENDOTHELIAL DYSFUNCTION IN PROGRESSION OF IDIOPATHIC INTERSTITIAL PNEUMONIAS (IIP)

TYPE: Abstract Publication TOPIC: Pulmonary Vascular Disease PURPOSE: The aim of our study was to define some mediators of ED and angiogenesis (endothelin1 (ET-1), vascular endothelial growth factor (VEGF), Plasminogen Activator Inhibitor-1 (PAI1) in patients with different clinical forms of IIP. METHODS: PATIENTS AND METHODS: 39 patients (22 – usual interstitial pneumonia, 17 – nonspecific interstitial pneumonia) with morphologically proved IIP were examined. Standard clinical examination, pulmonary function tests, echocardiography, high-resolution computed tomography (HRCT), measurement of diffusion capacity of the lung for carbon monoxide (DLCO) were evaluated. Plasma concentrations of ET-1, VEGF and PAI1 (ELISA) and morphometrics of lung biopsy for estimation of intensity of neoangiogenesis were performed. RESULTS: RESULTS: Markers of ED correlated positively with HRCT patterns of lung fibrosis (VEGF r=0,31, p=0,004; ET-1 r=0,37 p=0,003, PAI-1 r=0,38, р=0,006), the level of VEGF in the blood correlated with parameters of neoangiogenesis in the lung tissue (r=0,37, p=0,001). Patients with PH in comparison with patients without PH demonstrated higher concentrations of ЕТ-1 и PAI-1 (r=0,34, p=0,005 and r=0,37, р=0,002 respectively). Inverse correlation was established between PAI-1 and DLCO (r = -0,71, p<0,05), PAI-1 and FVC (r = -0,72, p<0,05). CONCLUSIONS: CONCLUSION: these data demonstrate the important role of the studied markers of ED and neoangiogenesis in the mechanisms of IIP progression and may be used as predictors of survival. CLINICAL IMPLICATIONS: Angiogenesis and endothelial dysfunction(ED) in idiopathic interstitial pneumonias(IIP) are considered as key mechanisms of lung tissue remodeling and pulmonary hypertension (PH). DISCLOSURE: No significant relationships. KEYWORDS: endothelial dysfunction, interstitial pneumonias

P0317EARLY MARKERS OF RENAL INJURY AND ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH METABOLIC SYNDROME

Abstract Background and Aims The definition of subclinical renal damage markers in patients with metabolic syndrome (MS) and evaluation the relations between the indicators of subclinical renal injury and endothelial dysfunction. Method The study included 62 patients with MS, 32 (51.6%) men and 30 (48.4%) women aged 51.2±5.4 years. The control group included 25 practically healthy individuals, 13 (52.0%) men and 12 (48.0%) women, aged 47.3±6.1 years. All patients were underwent clinical and laboratory examination, calculation of glomerular filtration rate (GFR) using the formula CKD-EPI, ultrasound of the carotid arteries, determination of the insulin resistance index (IR) (HOMA-IR), as well as determination of the content of endothelin-1 (ET-1) in serum and albumin excretion in a single portion of urine by IFA. Results When calculating GFR, hyperfiltration was detected in 10 (16.1%), optimal filtration - in 23 (37.1%), slightly reduced - in 29 (46.8%). At the same time, in patients with MS, a statistically significant excess of urinary albumin excretion (UAE) in a single dose was revealed compared with the control group (26.6±5.8 mcg/ml and 9.2±3.4 mcg/ml, respectively; p &amp;lt;0.001). Based on the increase in level (ET-1) in patients of the main group, compared with the control (6.3±3.2 fmol/ml and 3.4±1.0 fmol/ml, respectively; p=0.03) may indicate the development in patients of the main group of endothelial dysfunction. A correlation analysis revealed a direct correlation between the level of UAE and ET-1 (R = 0.45; p = 0.005). A direct correlation was found between UAE and IR-HOMA (R = 0.68; p &amp;lt;0.007), interventricular septum thickness (R = 0.71; p &amp;lt;0.001), and intima–media thickness (IMT) (R = 0.49; p &amp;lt;0.008) and systolic blood pressure (R = 0.47; p = 0.026). Similar associations were noted also for the ET-1 level: IR-HOMA2 (R = 0.78; p &amp;lt;0.001), with the thickness of the interventricular septum (R = 0.76; p = 0.001), IMT (R = 0.46; p &amp;lt;0.033) and systolic blood pressure (R = 0.45; p = 0.035). Conclusion In patients with metabolic syndrome, in addition to the well-known manifestations, in the early stages, may be a violation of renal function and endothelium, manifested by the change of glomerular filtration rate, increased levels of UAE and increased concentration of ET-1 in the blood. Direct correlation of the level of UAE and ET-1 level, and the coincidence of the correlation relationships of these indicators with a number of clinical and laboratory indicators of the metabolic syndrome will make it possible to consider an increasing of the level of UAE as one of the markers of endothelial dysfunction.

Altered protein levels in bone marrow lesions of hip osteoarthritis: Analysis by proteomics and multiplex immunoassays

To assess tissue level changes of proteome and cytokine profiles of subchondral bone in hip osteoarthritis (OA) affected by bone marrow lesions (BMLs). We compared significant protein level differences in osteoarthritic bone with BMLs to control bone without bone marrow lesions. Subchondral bone biopsies were taken from femoral heads of end-stage osteoarthritis patients with (BML, n=21) and without (CON, n=9) BMLs. Proteins were extracted through a standardized Trizol protocol and used in the subsequent analyses. Angiogenesis and bone markers were assessed using multiplex immunoassays (Luminex). Liquid chromatography tandem mass spectrometry (LC-MS/MS) was performed to detect significant differences in proteome and peptide profiles between BML and CON. Multiplex immunoassays revealed increased tissue contents of vascular endothelial growth factors (VEGF-A/C/D), endothelin-1, angiopoietin-2 and interleukin-6 (IL-6) in bone with BMLs compared to control bone, whereas osteoprotegerin levels were reduced. Mass spectrometry demonstrated pronounced increase in the levels of hemoglobin (73-fold), serum albumin (30-fold), alpha-1-antitrypsin (9-fold), apolipoprotein A1 (4.7-fold), pre-laminin-A/C (3.7-fold) and collagen-alpha1-XII (3-fold) in BMLs, while aggrecan core protein (ACAN) and hyaluronan and proteoglycan link protein 1 (HAPL1) decreased 37- and 29-fold respectively. Reduced osteoprotegerin, ACAN and HAPL1 are consistent with osteoclastic activation and high remodeling activity in BMLs. The pronounced increase in angiogenesis markers, hemoglobin and serum albumin support the presence of increased vascularity in subchondral bone affected by BMLs in OA. VEGFs and IL-6 are known nociceptive modulators, and increased levels are in keeping with pain being a clinical feature frequently associated with BMLs.

TGF-β1 promotes pulmonary arterial hypertension in rats via activating RhoA/ROCK signaling pathway.

To investigate the influence of the Rho/Rho-associated kinase (ROCK) signaling pathway in rats with pulmonary arterial hypertension (PAH) under the intervention with transforming growth factor-beta 1 (TGF-β1). A total of 30 rats were divided into three groups using a random number table, including control group (healthy rats, n=10), model group (PAH rats, n=10), and TGF group (PAH rats injected with 5 ng/mL TGF-β1 recombinant protein, n=10). The systolic blood pressure, ventricular hypertrophy index, pathological changes in lung tissues, TGF-β1 level, protein, and messenger ribonucleic acid (mRNA) expressions of RhoA and ROCK, as well as concentrations of serum nitric oxide (NO) and endothelin-1 (ET-1) were detected via hemodynamics test, hematoxylin and eosin (HE) staining, immunohistochemical method, reverse transcription-polymerase chain reaction (RT-PCR), and enzyme-linked immunosorbent assay (ELISA). The results of hemodynamics test showed that the right ventricular systolic pressure was increased markedly in model group (46.53±8.81) and TGF group (56.79±9.12) compared with that in control group (26.03±4.21) (p<0.05). The mean pulmonary systolic pressure in model group (25.89±1.92) and TGF group (29.41±1.91) was evidently higher than that in control group (15.77±2.71) (p<0.05). According to the results of heart weight measurement, model group (0.5118±0.1635) exhibited a higher ventricular hypertrophy index than control group (0.2908±0.0313) (p<0.05) but a lower ventricular hypertrophy index than TGF group (0.7231±0.1004) (p<0.05). The medial thickness of the pulmonary artery of the rats was observed through the HE staining. It was found that compared with control group, the medial thickness of the pulmonary artery was increased significantly in model group (p<0.05), while it was raised more prominently in TGF group, higher than that in model group, suggesting that TGF-β1 expression can increase the medial thickness of the pulmonary artery. It was manifested in immunohistochemical results that the protein expression of RhoA in the left lung tissues rose notably in model group compared with that in control group (p<0.05), and it was also raised remarkably in TGF group in comparison with that in model group (p<0.05), illustrating that the protein expression of TGF can activate the activity of RhoA and ROCK. The results of RT-PCR indicated that the mRNA expressions of RhoA and ROCK in the left lung tissues were elevated distinctly in model group and TGF group compared with those in control group (p<0.05), and the increases were more apparent in TGF group than those in model group (p<0.05). It was revealed in ELISA results that in comparison with control group, model group, and TGF group had markedly increased concentrations of serum NO and ET-1 (p<0.05), while the rises of serum NO and ET-1 concentrations in TGF group were the most prominent compared with those in model group (p<0.05). Overexpressed TGF-β1 can activate the RhoA/ROCK signaling pathway, thus promoting the occurrence and development of PAH.

Correlation between serum levels of endothelin-1 and disease severity in patients with neuromyelitis optica spectrum disorders

Neuromyelitis optica spectrum disorders (NMOSD) are aquaporin-4 antibody-mediated diseases of the central nervous system. Endothelin-1 (ET-1) is an inflammatory cytokine released by vascular endothelial cells and activated astrocytes. Previous studies have reported the aberrant expressions of cytokines/chemokines in patients diagnosed with NMOSD. However, the serum levels of ET-1 in NMOSD patients remain unknown. The purpose of this study was to measure the serum levels of ET-1 and other immune-related cytokines/chemokines in patients with NMOSD, and to investigate the correlation between serum ET-1 levels and clinical characteristics of NMOSD. Thirty-eight patients with NMOSD and twenty-eight healthy controls (HCs) were recruited in this study. The serum concentrations of ET-1 and other cytokines/chemokines were measured, and their correlations to the clinical features of patients with NMOSD were analyzed. The serum levels of ET-1 in patients with NMOSD were significantly higher than those in HCs (P = 0.0001). The serum concentrations of ET-1 were positively correlated with the Expanded Disability Status Scale score (r = 0.428, P = 0.0183). High-dose intravenous methylprednisolone treatment significantly reduced the levels of ET-1 and interleukin (IL)-6 in blood, but significantly increased the serum concentrations of IL-10 in NMOSD patients. No correlations were found between serum ET-1 levels and the concentrations of other cytokines/chemokines in these patients. ET-1 and IL-6 might exert pro-inflammatory effects in the pathogenesis of NMOSD, whereas IL-10 played an anti-inflammatory role in this process. ET-1 might be a potential biomarker for predicting the severity of NMOSD. However, the serum levels of ET-1 were not correlated with the changes of other cytokines/chemokines in patients with NMOSD. The involvement of ET-1 in the development of NMOSD needs to be further studied.

Activation of FXR receptor reduces damage of ET-1 on H9C2 cardiomyocytes by activating AMPK signaling pathway.

The aim of this study was to investigate the effect of Farnesoid X receptor (FXR) on oxidative stress injury of H9C2 cardiomyocytes induced by endothelin-1 (ET-1), and to explore the possible mechanism. H9C2 cardiomyocytes were treated with ET-1 at concentrations of 10-8, 10-7 and 10-6 mmol/L for 12, 24, 36, and 48 h, respectively. At the same time, oxidative stress injury models were established. After the oxidative stress injury model was established, GW4064 (FXR agonist), siRNA-FXR (the virus interfered with FXR expression) and FXR empty virus were treated for 48 h. CCK-8 method was used to observe the survival rate of cardiomyocytes. Biochemical kit method was used to detect Creatine Kinase (CK) contents, CAT, and mitochondrial activity. Western blot was used to detect the protein expression of SOD1, AMPK and p-AMPK. And real-time PCR was used to detect GPX1 mRNA, GPX3 mRNA, Sirt1 mRNA, PGC-1α mRNA expression levels. At the concentrations of 10-8, 10-7 and 10-6 mmol/L, ET-1 could induce the decrease of mitochondrial complex I and III activity and increase of CK content in H9C2 cardiomyocytes. Moreover, with the increase of ET-1 concentration and the extension of culture time, the oxidative stress damage of cardiomyocytes became more serious. After ET-1 intervention, the expressions of p-AMPK protein, Sirt1 mRNA and PGC-1α mRNA were decreased. The 2 μmol/L GW4064 could effectively improve the oxidative stress induced by ET-1, and compared with the ET-1 group, the survival rate of H9C2 cardiomyocytes increased obviously. In addition, the CK content was decreased. On the contrary, the mitochondrial complex I and III, and CAT activity increased significantly, and the expressions of SOD1 and p-AMPK protein, Sirt1 mRNA and PGC-1α mRNA increased obviously. However, siRNA-FXR can partially block the improvement effect of FXR agonist on cardiomyocytes injury. Activation of FXR receptor may reduce the damage of ET-1 on H9C2 cardiomyocytes by activating AMPK signaling pathway.

Endothelial function in pregnant women with chronic hypertension and abdominal obesity

Objective. To evaluate endothelial function in pregnant women with chronic hypertension and abdominal obesity. Material and Methods. We studied 30 pregnant women with chronic hypertension and abdominal obesity (group I), 28 pregnant women with chronic hypertension and normal body mass index (group IIa), 27 pregnant women with abdominal obesity without chronic hypertension (group IIb), and 33 pregnant women without chronic hypertension and abdominal obesity (control group). We performed reactive hyperemia tests, assessed the serum levels of endothelin-1 and homocysteine, and analyzed the outcomes of pregnancy and delivery. Results. The values of endothelium-dependent vasodilation (EDVD) in pregnant women of groups I, IIa, and IIb were comparable and were 6.7 (3.2–9.1)%, 7.0 (3.9–11.4)%, and 7.2 (4.4–10.8)%, respectively. Significant differences were found in EDVD values between the groups mentioned above and the control group, where the EDVD value was 12.5 (10.5–13.9)%, p &lt; 0.05. The endothelin-1 concentration in group I was 14.0 (10.3–17.5) pg/mL, which significantly exceeded the corresponding values in group IIa ( p &lt; 0.05) and the control group ( p &lt; 0.05). The endothelin-1 level in patients with abdominal obesity was twice higher than the corresponding value in the control group ( p &lt; 0.05). Significant differences were observed between patients with chronic hypertension (groups I and IIa) and control group ( p &lt; 0.05). The level of homocysteine in control group [6.1 (3.9; 8.0) µmol/L] significantly differed from the corresponding values in group I [9.3 (7.8; 10.5) µmol/L, p &lt; 0.05], group IIa [7.8 (6.8; 9.8) µmol/L, p &lt; 0.05], and group IIb [7.8 (6.8; 9.8) µmol/L, p &lt; 0.05]. Conclusions. This study showed the presence of endothelial dysfunction in pregnant women with chronic arterial hypertension and abdominal obesity. This observation was confirmed by the lower values of EDVD, higher frequency of attenuated and paradoxical responses to the reactive hyperemia test, and the elevated serum levels of homocysteine and endothelin-1 in this category of patients. The endothelial dysfunction contributed to the development of pregnancy complications and adverse outcomes of pregnancy compared with the control group and women who had isolated manifestations of chronic hypertension and abdominal obesity.

The relationship of endothelial vasoregulation factors and the state of the antioxidant system with manifestations of rheumatoid arthritis

The aim of the work was to identify the relationship of vasomotor and angiogenic factors of the endothelium, as well as the state of the antioxidant system in rheumatoid arthritis (RA). Materials and methods included 50 patients with RA and 42 healthy people of appropriate age and gender, who analyzed the main clinical indicators. In erythrocytes, the activity of superoxide dismutase (SOD), glutathione peroxidase (GPO), glutathione reductase (GR) and the concentration of reduced glutathione (GSH) were investigated. The concentration of higher nitrogen oxides (NOx), endothelin-1 (ET-1) and vascular endothelial growth factor VEGF-A was determined in plasma. Results . In the general group of patients with RA, signs of oxidative stress (OS) were observed, expressed in a decrease in the activity of GPO, GR and SOD when compared with the control, and a positive correlation of ET-1 with VEGF-A (R=0.547, p=0.028) and ET-1 with RF ( R=0.578; p=0.024). ET-1 (R=0.622; p=0.031) and VEGF-A (R=0.627; p=0.016) correlated with the presence of joint erosion. Among patients with joint erosion, the level of VEGF-A correlated with the activity of the process (R=0.756; p=0.030), the level of plasma NOx (R=0.545; p=0.036) and the activity of GR (R=0.579; p=0.03). The ET-1 level in the blood plasma of patients with RA with joint erosion was 10.0 (4.4–10.0) ng / l and was higher than in patients without erosion (4.2 (2.3–17) ng/l). The level of plasma VEGF-A in patients with RA with joint erosion (62.8 (31.0–100.0) ng /l) was higher than in patients without erosion (20.4 (10.0–25.3) ng/l). Conclusions . A decrease in the concentration of GSH and the activity of GPO, GR and SOD indicate the presence of OS in patients with RA, regardless of the duration and activity of the disease. ET-1 and VEGF-A may be prognostic criteria for erosive RA.

Regulation of PI3k-WNK Pathway by Ethyl Acetate Partition Fraction of Gardenia jasminoides var. radicans Makino in SHR, NRK52e Cells, and IMCD3 Cells

The antihypertensive mechanism was studied of the ethyl acetate fraction of the ethanol extract (EAPF) of Gardenia jasminoides var. radicans Makino (GJRM). GJRM is a fake product of Gardenia jasminoides Ellis ( G. jasminoides), but in China’s Henan province, the production of GJRM is much more than G. jasminoides’s, but its traditional usage is as a dye. Gardenia jasminoides can be used to reduce blood pressure and blood glucose levels. The chemical compositions of GJRM and G. jasminoides are similar, and we previously confirmed that GJRM can also reduce blood pressure. Here, we report that the EAPF of GJRM could activate the phosphoinositide 3-kinases (PI3K) pathway in the kidneys of spontaneously hypertensive rats, thus increasing the content of nitric oxide and bradykinin in sera and decreasing endothelin-1 content. EAPF can also decrease the levels of with-no-lysine kinase 1 (WNK1) expression, WNK4 and oxidative stress-responsive kinase 1 messenger ribonucleic acid (mRNA), and Na-K-2Cl cotransporter and sodium chloride cotransporters mRNA and phosphorylation. To investigate the antihypertensive effects of the EAPF of GJRM, 5 monoterpenoids isolated from EAPF were studied for their effects on NRK52e and IMCD3 cells. These compounds inhibited the PI3K-WNK signaling pathway to varying degrees under hypotonic conditions; 4-methoxyrehmapicrogenin had the best effect.

High-dose atorvastatin improves vascular endothelial function in patients with leukoaraiosis.

ObjectiveLeukoaraiosis (LA), as an age‐related white matter degeneration, is mainly caused by chronic ischemia. Our study aims to explore the efficacy of different doses of atorvastatin (ATV) in the vascular endothelial function in patients with LA.MethodsOur study enrolled 402 LA patients who were then randomly included as control or treated with ATV (10 mg), ATV (20 mg), or ATV (30 mg). The total cholesterol (TC), triglycerides (TG), high‐density lipoprotein cholesterol (HDL‐C), and low‐density lipoprotein cholesterol (LDL‐C) were detected by enzyme colorimetric assay. The high‐sensitivity C‐reactive protein (hs‐CRP) level, reactive hyperemia index (RHI), endothelin‐1 (ET‐1) content, and nitric oxide (NO) level were tested by latex agglutination test, peripheral arterial tonometry technology, radioimmunoassay, and nitrate reductase assay, respectively.ResultsAfter 8 weeks of ATV treatment, the levels of TC, LDL‐C, and HS‐CRP decreased significantly, and the trends were demonstrated in a more significant way with the increases of dose of ATV. The treatment with ATV at different doses elevated NO level and RHI and declined ET‐1 content. Gastrointestinal reaction, muscular pain, and increased aminopherase were observed after treatment with the ATV at different doses with more obvious symptoms detected accompanied by the increase of the dose. The RHI was in negative correlation with the ET‐1 and HS‐CRP while in positive correlation with NO.ConclusionOur study demonstrates that ATV can significantly improve the vascular endothelial function in LA patients with a dose‐dependent effect.

Expediency of сitoprotective treatment of patients with acute myocardial infarction, who were performed percutaneous coronary intervention

The aim of the study was to increase the efficiency of treatment of patients with Acute Miocardial Infarction by incorporating the protocol therapy for the course of parenteral use of L-arginine and L-carnitine.Material and methods.A total of 45 patients with acute coronary syndrome with ST segment elevation were investigated, who had undergone urgent balloon angioplasty and stenting of a heart attack-dependent coronary artery. The study selected patients aged on average (59,57 ± 8,07) years. The experimental group consisted of 30 patients, who received standard protocol treatment of ACS (MI) and additionally were prescribed 4.2 g L-arginine and 2.0 g L-carnitine in the 100 ml solution for infusion once daily for 5 days intravenously. The control group included 15 patients with ACS (MI) who also had percutaneous coronary intervention, but this group received only standard protocol treatment.In addition to general clinical, instrumental and laboratory methods (general blood test, MB Creatinephosphokinase fraction (CFC-MB), Troponin T, oxygen saturation of arterial blood (SpO2), ECG in 12 standard leads, etc.), performed an echocardiography in the B-mode with the definition of linear and volume indicators of the left ventricle, as well as the global (by the ejection fraction (EF) and local contractile activity of the myocardium by the Simpson method. The functional state of the vascular endothelium was determined by the concentration of endothelin-1 (ET-1) in the blood plasma and the content of stable NO metabolites [5]. The determination of endothelin-1 (ET-1) in serum was carried out using for determining the ultimate stable metabolites of NO in the blood. Results. It has been established that patients with ACS (MI) after percutaneous coronary intervention often develop reperfusion syndrome with manifestations of left ventricular insufficiency and rhythm disturbances. Substantial clinical and functional improvement was noted under the influence of standard medical treatment in patients of control group. At the same time postinfarction remodeling with systolic and diastolic function of the heart, with the development of heart failure syndrome and endothelial dysfunction of blood vessels, and also remained resistant to extrasystole therapy, progressed.Patients in the experimental group under the influence of complex medical treatment with the inclusion of L-arginine and L-carnitine marked a significant decrease in the frequency of violations of rhythm and conduction for the second day of observation, as well as a decrease in the manifestations of post-infarction remodeling of LV, which ultimately manifested a significant improvement in myocardial contractility (EF increased by 13%) and decreased diastolic dysfunction. Improvement of the inotropic function of the heart and a significant reduction in the frequency and severity of reperfusion arrhythmias was achieved precisely due to cardiometabolic effects of L-carnitine. In addition, in patients undergoing additional treatment with L-arginine and L-carnitine after 10 days of treatment, the activity of ET-1 was significantly lowered and the concentration of nitrogen oxide metabolites in the blood plasma increased and reach the level of healthy subjects (P&gt; 0,05). So, they recovered the endothelial function of the vessels.Conclusions: In the first day after percutaneous coronary intervention on the background of standard drug therapy was most often diagnosed with reperfusion syndrome with manifestations of acute left ventricular failure and arrhythmias and conduction.The use of complex drug therapy with the inclusion of L-arginine and L-carnitine on the background of an individualized cardiorehabilitation program led to a significant improvement in the parameters of central cardiohemodynamics and restoration of vascular endothelial function, was accompanied by a significant decrease in the frequency of development and severity of such complications of ACS (MI) as reperfusion arrhythmias and acute left ventricular failure.