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PURPOSE Retinal vein occlusion (RVO) risk factors largely coincide with cardiovascular risk factors. Endothelin-1 (ET-1), the most potent vasoconstrictor with pro-inflammatory properties, is a known cardiovascular risk factor. In this study, we explore the role of serum ET-1 as a potential risk factor for RVO. METHODS ET-1 serum levels were measured in patients with RVO and control subjects. Samples were measured using the sandwich enzyme-linked immunosorbent assay (ELISA) for the quantitative determination of human big endothelin-1 (Biomedica Group, Austria). RESULTS The study consisted of 147 RVO patients and 150 control subjects. Median serum ET-1 was significantly higher in RVO patients (0.26 pmol/L, ranging 0.19-0.37) compared to controls (0.10 pmol/L, ranging 0.05-0.22) (p

To assess the impact of our transcranial Doppler (TCD) screening program on the incidence of a first stroke in children with sickle cell anemia and to study the role of elevated serum endothelin-1 (an inflammatory mediator) in these children. Background: stroke is a major complication of sickle cell disease (SCD), even in very young children. About 11% of children with homozygous sickle cell anemia (SS) develop stroke by the end of the second decade of life. The underlying etiology in most cases is an ischemic stroke caused by large-vessel stenosis or occlusion. Transcranial Doppler (TCD) recommended as a routine screening test to identify children at high risk of developing a stroke, measures flow velocities within large intracranial arteries. TCD should be routinely performed in children between 2 and 16 years as this age group is at the highest risk of sickle cerebral vasculopathy. We carried out a prospective case-control study which included 2 groups: a patient group consisted of 30 children with sickle cell anemia and sickle thalassemia and a group of 30 healthy children of matched age and sex. Each group included 11 males (36.5%) and 19 females (63.5%); the age range was 2 to 17 years. Both groups underwent a thorough clinical examination and laboratory tests (CBC, liver and renal function, serum ferritin and endothelin-1). Additionally, TCD was performed in all children included in the patient group. According to the results of TCD, time-averaged mean of the maximum velocity (TAMMX) was < 170 cm/s (normal), 170–200 cm/s (conditional), ≥ 200 cm/s (high risk) in 20 (66.7%), 4 (13.3%) 6 (20%) patients, respectively. The level of endothelin-1 was significantly higher in the patients (57.1 ± 91.3) than in the controls (21.9 ± 14.8). Hemoglobin concentration was significantly lower in the patient group than in the control group, but the levels of reticulocytes, WBCs and serum ferritin were significantly higher in the patients than in the healthy controls. Serum Endotheline-1 level was higher in patients with sickle cell anemia than control group.

Aim. To assess the change in the concentration of endothelin-1 (ET-1) and the state of uteroplacental blood flow in women in the third trimester of gestation with exacerbation of cytomegalovirus infection (CMVI) in the second trimester of pregnancy.Materials and methods. A comprehensive examination of 120 women with pregnancies uncomplicated and complicated by exacerbation of CMVI in the second trimester of gestation was carried out. The first group consisted of 30 women with a seronegative CMVI normal pregnancy, the second group – 30 patients with a latent course of CMVI and the development of chronic compensated placental insufficiency (CCPI), the third – 30 women with exacerbation of CMVI and CCPI, and the fourth – 30 patients with exacerbation of CMVI and chronic subcompensated placental insufficiency (CSPI).Results. With the development of CCPI at 30-34 weeks of gestation in women of the second group, compared with the first, the concentration of ET-1 in blood serum increased to 1.16±0.09 fmol/L (in the control – 0.86±0.08 fmol/L, pConclusion. The development of CSPI in the third trimester of gestation in women who underwent an exacerbation of CMVI in the second trimester of pregnancy, in contrast to CCPI with a similar infectious pathology in pregnant women, is characterized by a more pronounced increase in vascular resistance in the uterine artery basin against the background of endothelial dysfunction.

Актуальность. В последние годы многие ученые подчеркивают определяющую роль сосудистой стенки в регуляции агрегатного состояния крови, а также значение ее нарушений в развитии заболеваний пищеварительной системы. Однако до настоящего времени отсутствуют данные о роли Helicobacter pylori в развитии эндотелиальной дисфункции. Цель: оценить характер изменений уровня оксида азота (NO) и эндотелина-1 в крови детей при эрозивно-язвенных поражениях верхних отделов желудочно-кишечного тракта. Материалы и методы. Проведено комплексное клиническое и инструментально-лабораторное обследование 120 детей с хроническим эрозивным гастродуоденитом (79 человек) и язвенной болезнью двенадцатиперстной кишки (41 человек) в возрасте 7–18 лет (основная группа) и 50 детей соответствующего возраста без патологии пищеварительной системы (группа сравнения). Всем детям проводилось тщательное клинико-параклиническое исследование по общепринятым в клинике методикам. Концентрацию нитритов в плазме крови определяли по методике П.П. Голикова (2004). Исследование уровня эндотелина-1 в сыворотке крови проводилось с помощью метода иммуноферментного анализа с использованием наборов фирмы Biomedicagruppe (Германия). Результаты исследования представлены количеством наблюдений в группе, процентами или средним и среднеквадратичным отклонением, точным значением р. Результаты. Дети были распределены по возрасту, полу, месту жительства и нозологической форме патологии. Уровень NО в плазме крови детей основной группы был достоверно ниже и составлял 11,78 ± 1,10 мкмоль/л, р < 0,05. При внутригрупповом анализе в обеих группах обследованных детей достоверной разницы между содержанием NО в крови в зависимости от пола и возраста не выявлено (р > 0,05). При отсутствии Helicobacter pylori уровень NО в крови достоверно выше по сравнению с группой больных, в которой диагностирована Helicobacter pylori-ассоциированная патология (р < 0,05). Выявлена разница в уровнях NO в крови детей в зависимости от периода болезни: его уровень выше в период обострения как хронического эрозивного гастродуоденита, так и язвенной болезни двенадцатиперстной кишки. В среднем у детей основной группы уровень эндотелина-1 в крови был достоверно ниже такового у детей группы сравнения — 0,36 ± 0,02 фмоль/мл и 0,48 ± 0,02 фмоль/мл соответственно, p < 0,01. Уровень эндотелина-1 в крови детей также зависел от наличия Helicobacter pylori. Выводы. Уровни метаболитов NО и эндотелина-1 достоверно снижены в крови детей с эрозивно-язвенной патологией верхних отделов желудочно-кишечного тракта, зависят от периода заболевания и наличия Helicobacter pylori и не зависят от возраста и пола.

Background . The renal endothelium is the primary barrier which reacts to systemic endothelial vascular dysfunction in patients with rheumatic diseases. The objective of the work was to evaluate the nature of morphological changes in the endothelium of renal capillaries and arterioles in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), hemorrhagic vasculitis (HV) and microscopic polyangiitis (MPA), the relationship with clinical and laboratory factors of the disease course and the impact of systemic vascular endothelial dysfunction. Materials and Methods. Retrospective analysis of nephrobiopsy results in comparison with laboratory findings of endothelial vascular dysfunction (EVD) was performed in 94 patients (41 subjects with SLE, 17 — RA, 24 — HV and 12 — MPA). Results. EVD takes place in 39 patients with SLE, 35 — RA, 52 HV and MPA, and in 100 % of those who develop nephropathy. It is closely associated with systemic clinical and instrumental manifestations of angiopathy, and proliferation of capillary endothelium and renal arterioles, depositions in it of immunoglobulins and complement components; depending on the clinical entities of systemic autoimmune rheumatic diseases it determines the blood levels of vascular endothelial growth factor (VEGF), endothelin 1 (ET1), homocysteine, E- and P-selectin. EVD in the form of an imbalance of VEGF, ET1, thromboxane A2 (TxA2) and prostacyclin (PgI2) vasodilators occurs in 35 % of RA patients with renal damage, 39 % have SLE, 52 % — HV and 100 % — MPA. Three-dimensional integrated histograms of vasoconstrictors (VEGF + ET1 + TxA2) in patients with renal failure are presented. Conclusions . EVD is probably participating in the pathogenesis of endothelial changes in capillaries, glomeruli and arterioles. Morphological endothelium damage of the renal vessels is closely related to the severity of the clinical and instrumental features of systemic extrarenal angiopathy (damage to the skin, mucous membranes and peripheral nervous system, parameters of biomicroscopy of the vessels of the conjunctiva and vasodilation of the brachial artery). Proliferation of the glomerular endothelium in patients with MPA determines the serum concentration of VEGF; ET1 and ESel are involved in the development of renal immune endothelial deposits (IgA, IgG, IgM, C3, C1q) in lupus glomerulonephritis.

Multikinase inhibitors, such as sorafenib, are used for the treatment of advanced carcinomas but the response shows limited efficacy or varies a lot with patients. Here we adopted the systems approach combined with high-throughput data analysis to discover key mechanism embedded in the drug response. When analyzing the transcriptomic data from the Cancer Cell Line Encyclopedia (CCLE) database, endothelin 1 (EDN1) was enriched in cancer cells with low responsiveness to sorafenib. We found that the level of EDN1 is higher in the tissue and blood of hepatocellular carcinoma (HCC) patients showing poor response to sorafenib. In vitro experiment showed that EDN1 not only induces activation of angiogenic-promoting pathways in HCC cells but also stimulates proliferation and migration. Moreover, EDN1 is related with poor responsiveness to sorafenib by mitigating unfolded protein response (UPR), which was validated in both transcriptomic data analysis and in silico simulation. Finally, we found that endothelin receptor B (EDNRB) antagonists can enhance the efficacy of sorafenib in both HCC cells and xenograft mouse models. Our findings provide that EDN1 is a novel diagnostic marker for sorafenib responsiveness in HCC and a basis for testing macitentan, which is currently used for pulmonary artery hypertension, in combination with sorafenib in advanced HCC patients.

BACKGROUND Hypertension is common in hemodialysis (HD) patients. Increased blood pressure (BP) variability, particularly higher and lower extremes, is associated with adverse outcomes. We explored the association of endothelin-1 (ET-1), a potent vasoconstrictor, with different BP parameters (pre-HD, intra-HD, and post-HD) during HD in a contemporary patient cohort. METHODS This study uses the DaVita Biorepository, a longitudinal prospective cohort study with quarterly collection of clinical data and biospecimens. Unadjusted and adjusted linear mixed effects regression models were fit to determine association of pre-HD ET-1 (log-transformed and quartiles) with HD-related systolic BP (SBP) parameters (pre-HD, nadir intra-HD, and post-HD). As ET-1 was measured at baseline, analyses were restricted to 1 year of follow-up. RESULTS Among 769 participants, mean age was 52 years, 42% were females, and 41% were Black. Mean pre-HD SBP was 152 (±28) mm Hg and mean ET-1 concentration was 2.3 (±1.2) ng/ml. In fully adjusted models, each unit increase in SD of log-transformed ET-1 was associated with a 2.7 (95% confidence interval [CI] 1.5, 4.0) mm Hg higher pre-SBP; 1.6 (95% CI 0.9, 2.3) mm Hg higher nadir SBP; and 2.0 (95% CI 1.1, 2.9) mm Hg higher post-SBP. Each SD increase in log-transformed ET-1 was associated with 21% higher odds of experiencing intradialytic hypertension (odds ratio 1.21; 95% CI 1.10–1.34). CONCLUSIONS Higher baseline ET-1 levels are independently associated with higher SBP and higher odds of intradialytic hypertension. These results highlight a potential role for ET-1 in BP control in HD patients and raise the possibility of ET-1 antagonism as a therapeutic target.

Heated tobacco products (HTP) were introduced to the world market as an alternative to conventional tobacco cigarettes. Active advertising, readily available to purchase and the public's perception that HTP are a safer alternative to conventional tobacco cigarettes lead to increasing their consumption by young age group in Ukraine. Despite the claims by the tobacco corporations about reduction of adverse effects the HTP on the activity of cardiovascular system, the published studies of potential vascular endothelial consequences were not found. Therefore, the aim of our study is to assess the HTP effect on vascular endothelial cells by determination of the nitrate, nitrite, S-nitrosothiols, and endothelin-1 levels in saliva of smoking adolescents. The object and research methods. Thirty adolescents aged 14-17 years old were divided to three groups. Group I was introduced by ten healthy non-smoking adolescents (control group). Group II consists of ten smoking adolescents have smoked the IQOS for two years. Group III is formed by ten smoking adolescents who have smoked the IQOS for three years. The salivary nitrate and nitrite levels were measured using the Griess assay such as an indicator of NO production. The salivary S-nitrosothiols were measured spectrophotometrically. The salivary endothelin-1 level was measured with ELISA kit. Statistical analysis of the data was carried out using the STATISTICA 7.0 program. The data were presented as Median values (Me), lower and upper quartile, i.e. Me [Lq; Uq]. Statistical significance was accepted if p < 0.05. Results. The salivary nitrate concentrations in groups II (Me = 14.11 [13.98; 14.52] μmol/l) and III (Me = 12.06 [11.44; 12.31] μmol/l) were significantly decreased compared to group I (Me = 15.89 [14.98; 16.89] μmol/l, KW test: H = 23.59, p=0.000. The values of nitrite in groups II and III were the following: Me = 2.32 [1.47; 2.48] μmol/l and 1.37 [1.25; 1.44] μmol/l, respectively. The indices were lower in 1.41 and 2.36 times than in group I: Me = 3. 24 [3.05; 3.78] μmol/l, KW test: Н = 22.92, p = 0.000. The levels of salivary S-nitrosothiols in group II are: Me = 1.02 [0.84; 1.27] μmol/l and group III Me = 0.36 [0.25; 0.62] μmol/l were reduced in 1.75 and 4.97 times compared to group I: Me = 1.79 [1.67; 1.97] μmol/l, KW test: Н = 24.46, р = 0.000. We assume that the reduction of salivary nitrate and nitrite concentrations is associated with a low level of S-nitrosothiols which serve as deposited and released nitric oxide (NO). Probably, the decrease of nitrates and nitrites is associated with the inhibition of endothelial NO synthase. The salivary endothelin-1 level was significantly higher in group II: Ме=0.58 [0.53; 0.73] pmol/ml and in group III: Ме = 0.82 [0.79; 0.93] pmol/ml than in group I: Ме = 0.17 [0.14; 0.26] pmol/ml, KW test: Н = 23.94, р = 0.000. It should be noted, the significant differences between data of nitrate, nitrite, S-nitrosothiol and endothelin-1 content in groups II and III were found (Mann-Whitney U test, nitrates - Z = 3.62, p = 0.000; nitrites - Z = 2.91 , p = 0.003; S-nitrosothiols - Z = 3.74, p = 0.00; endothelin-1 - Z = 3.36, p = 0.000). These results showed interrelation between adverse IQOS effect on vascular endothelium of adolescents duration of IQOS smoke. Conclusions. The adverse effect of heated tobacco product (IQOS) on the biochemical indicators of the vascular endothelium function of adolescents was found in our experimental study. The salivary nitrate, nitrite and S-nitrosothiols levels were significantly decreased in IQOS smoking adolescents. The salivary endothelin-1 content was significantly elevated in IQOS smoking adolescents. The revealed changes indicate the endothelial dysfunction in young smokers. The development of pathological processes in the vascular endothelium depends on the smoking duration.

AIMS Better understanding of the timeline and risk factors for the appearance of complications in pediatric Type-1-diabetes is key for developing prevention strategies. We studied endothelial markers and their determinants in adolescents with Type-1-diabetes at different time points from diagnosis. METHODS A cross-sectional study of 58 adolescents, mean age 15.0 ± 2.4 years; 20 with recent-onset Type-1-diabetes, 20 with over 7 years of Type-1-diabetes and 18 controls. Clinical and biochemical data were collected. Fingertip arterial reactive hyperemia (EndoPAT) and carotid intima-media-thickness (cIMT) were measured to assess endothelial function and structure. RESULTS Compared to controls, individuals with prolonged Type-1-diabetes had higher mean cIMT (0.49 ± 0.07 mm vs. 0.43 ± 0.05 mm p = 0.021) and maximal cIMT (0.61 ± 0.08 mm 0.52 ± 0.08 mm, p = 0.025). Endothelin-1 levels were significantly lower in subjects with prolonged Type-1-diabetes (1.2 ± 1.0 pg/ml) compared to controls (3.0 ± 1.7, p = 0.008 pg/ml); they negatively correlated with the mean cIMT (c = - 0.291, p = 0.031) and mean 6 months hemoglobin A1c (c = - 0.301, p = 0.022) and positively correlated with mean c-peptide levels (c = 0.356, p = 0.006) and the weekly exercise time (c = 0.485, p

Our research goal was to reveal peculiarities related to changes in endothelin-1 contents in blood serum in young and middle-aged people exposed to occupational noise and industrial welding and silicon-containing aerosols with fibrogenic effects. Another goal was to establish a correlation between endothelin-1 contents and blood pressure, body mass, and dyslipidemia. We examined workers employed at a metallurgic plant in Nizhniy Novgorod region. Endothelin-1 concentration in blood serum was determined with «Endothelin (1-21)», a reagent kit for ELISA produced by «Biomedica Medizinprodukte GmbH & Co KG» (Austria). We detected certain group differences in endothelin-1 contents in blood serum and frequency of its elevated concentrations between workers who had to work under different working conditions. We established a direct correlation between endothelin-1 and blood pressure, total cholesterol, and body mass index. Elevated endothelin-1 contents in people suffering from arterial hypertension can indicate a higher risk of complications this disease might have. People who have elevated endothelin-1 contents but normal blood pressure, total cholesterol within physiological standard and normal body mass index can be recommended to have regular medical check-ups focusing on functional state of their cardiovascular system; endothelin-1 in this case should be considered a risk factor that might cause cardiovascular pathology occurrence. An individual approach is required when assessing elevated endothelin-1 contents and probable use of this parameter as a risk factor that might cause cardiovascular pathology in young and middle-aged people employed under hazardous working conditions.

Hypertensive kidney injury (Hki) is one of the most common complications of hypertension. Early prevention and treatment of renal injury in patients with hypertension is great significance. The study, which used an integrated ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS) analysis, network pharmacology approach, and plasma metabolomics, aimed to discover the active ingredients and therapeutic mechanisms of Eucommiae folium (Ef) in treating Hki. The chemical components of Ef were analyzed by UPLC-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS), and the "compound-target-disease" network was constructed by screening the closely related drug targets from the drug-target database, then the signaling pathways related to Hki were analyzed. Finally, the enzyme-linked immunosorbent assay (ELISA) and real-time quantitative reverse-transcription polymerase chain reaction were used to test and verify the key targets in the common pathways of metabolomics and network pharmacology. The results indicated that Eucommiae folium might play an excellent role in treating Hki, likely through regulating the vascular endothelial growth factor signaling pathway, hypoxia inducible factor 1 (HIF-1) signaling pathway, and glycerophospholipid metabolism pathway, which were validated by increasing levels of nitric oxide, endothelial nitric oxide synthase and reducing levels of endothelin 1, angiotensin II, renin, cyclic guanosine monophosphate, blood urea nitrogen, and serum creatinine, as well as the reduced gene expression of Ache, Ddah2, Egfr, Lcat, Pla2g2a, Stat3 and Vegfa. The study systematically explored the protective mechanisms of Ef against Hki and also provided the practical treatment strategies of Hki from the Chinese herb.

Ischemia is one of the most common causes of acquired brain injury. Central to its noxious sequelae are spreading depolarizations (SDs), waves of persistent depolarizations which start at the location of the flow obstruction and expand outwards leading to excitotoxic damage. The majority of acute stage of stroke studies to date have focused on the phenomenology of SDs and their association with brain damage. In the current work, we investigated the role of peri-injection zone pyramidal neurons in triggering SDs by optogenetic stimulation in an endothelin-1 rat model of focal ischemia. Our concurrent two photon fluorescence microscopy data and local field potential recordings indicated that a ≥ 60% drop in cortical arteriolar red blood cell velocity was associated with SDs at the ET-1 injection site. SDs were also observed in the peri-injection zone, which subsequently exhibited elevated neuronal activity in the low-frequency bands. Critically, SDs were triggered by low- but not high-frequency optogenetic stimulation of peri-injection zone pyramidal neurons. Our findings depict a complex etiology of SDs post focal ischemia and reveal that effects of neuronal modulation exhibit spectral and spatial selectivity.

Rheumatoid arthritis (RA) patients suffer from the effects of acute and chronic inflammation, and it can be deteriorated by the production of endothelin-1, which is a pro-inflammatory molecule and participates in the pathogenesis of RA. Bee venom (BV) with low doses plays an anti-inflammatory role in the treatment of RA. Besides, nano-emulsions (NEs) increase topical drug delivery and its effectiveness. This project was designed to explore the effects of nano-emulsions containing bee venom (Top-NEs) on the serum level of endothelin-1 in the rats of the collagen-induced RA (CIA) model. After induction of CIA in Wistar rats and grouping, the serum levels of endothelin-1 were measured in four steps. In healthy rats on day 0, in CIA model before, middle, and at the end of treatment on days 7, 14, and 21, respectively. The results demonstrated that serum levels of endothelin-1 had significantly increased in CIA rats before treatment, and they were more in the middle and the end of treatment about blank and negative control groups. However, they had significantly decreased in the Top-NEs groups in the middle and the end of treatment. Topical NEs containing BV can ameliorate the serum level of endothelin-1 in the CIA model; in addition, they can pass BV through the skin. Also, it appears that endothelin-1 can be considered as the main target for the treatment of RA.

IntroductionEndothelin-1 (ET-1) is the most potent among all vasoconstrictors, and its association with cardiovascular diseases has been reported before. Our aim was to investigate the association of ET-1 plasma level and its gene polymorphisms (rs5370 and rs10478694) with hypertension and coronary atherosclerosis (CA).Material and methodsThis study was carried out on 128 women and 132 men, who were divided into 4 groups: hypertensive without atherosclerosis (H+A–); hypertensive with atherosclerosis (H+A+); non-hypertensive with atherosclerosis (H–A+); and non-hypertensive without atherosclerosis (control group). Endothelin-1 plasma levels were measured by ELISA, and gene polymorphisms were detected by polymerase chain reaction – restriction fragment length polymorphism (PCR-RFLP) methods. Coronary artery diseases (CAD) were then defined based on angiography data.ResultsThe ET-1 plasma level was significantly higher in the H+A+ group in comparison with the other groups, especially H+A–. Comparing people with CA and those without it, the highest frequency level of the T allele of rs5370 was found in people with CA. Significantly higher frequencies of the 3A allele were detected in hypertensive patients in comparison with non-hypertensive individuals, when analyzing rs10478694.ConclusionsEndothelin-1 plasma level shows a direct association with the risk of CA development. The T allele of rs5370 can be regarded as a risk factor for CA development. The 3A allele of rs10478694 can be associated with the risk of hypertension; therefore, it can be concluded that ET-1 and its gene polymorphisms play an important role in CA development and hypertension observed in the south-eastern populations of Iran.

Polycythemia and pulmonary hypertension are 2 human diseases for which better therapies are needed. Upregulation of hypoxia-inducible factor-2α (HIF-2α) and its target genes, erythropoietin (EPO) and endothelin-1, causes polycythemia and pulmonary hypertension in patients with Chuvash polycythemia who are homozygous for the R200W mutation in the von Hippel Lindau (VHL) gene and in a murine mouse model of Chuvash polycythemia that bears the same homozygous VhlR200W mutation. Moreover, the aged VhlR200W mice developed pulmonary fibrosis, most likely due to the increased expression of Cxcl-12, another Hif-2α target. Patients with mutations in iron regulatory protein 1 (IRP1) also develop polycythemia, and Irp1-knockout (Irp1-KO) mice exhibit polycythemia, pulmonary hypertension, and cardiac fibrosis attributable to translational derepression of Hif-2α, and the resultant high expression of the Hif-2α targets EPO, endothelin-1, and Cxcl-12. In this study, we inactivated Hif-2α with the second-generation allosteric HIF-2α inhibitor MK-6482 in VhlR200W, Irp1-KO, and double-mutant VhlR200W;Irp1-KO mice. MK-6482 treatment decreased EPO production and reversed polycythemia in all 3 mouse models. Drug treatment also decreased right ventricular pressure and mitigated pulmonary hypertension in VhlR200W, Irp1-KO, and VhlR200W;Irp1-KO mice to near normal wild-type levels and normalized the movement of the cardiac interventricular septum in VhlR200Wmice. MK-6482 treatment reduced the increased expression of Cxcl-12, which, in association with CXCR4, mediates fibrocyte influx into the lungs, potentially causing pulmonary fibrosis. Our results suggest that oral intake of MK-6482 could represent a new approach to treatment of patients with polycythemia, pulmonary hypertension, pulmonary fibrosis, and complications caused by elevated expression of HIF-2α.

BACKGROUND Mechanisms of exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF) are not well understood. Pulmonary hypertension, a common accompaniment in patients with HFpEF, is associated with poor outcomes. While Endothelin -1 (ET-1) plays a mechanistic role in pulmonary hypertension, its role in exercise intolerance in HFpEF is not well established. OBJECTIVE To explore the association between plasma ET-1 levels and maximal oxygen consumption (pVO2), and their changes over 24 weeks in HFpEF. METHODS This is a post-hoc analysis of the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial. We performed linear regressions to assess the relationship between plasma ET-1 and pVO2. We also used linear regressions to determine whether ET-1 was associated with change in peak VO2 (ΔpVO2). RESULTS A total of 210 patients were included. Baseline plasma ET-1 levels were associated with older age, higher NT-proBNP levels, higher serum creatinine levels, and higher prevalence of atrial fibrillation. Patients with higher ET1 levels also had higher plasma galectin-3 and CITP levels. After multiple adjustments, baseline ET1 levels were associated with lower pVO2 (β -0.927, SE 0.196, p

Objective Endothelin-1 plays an important role in the pathogenesis of severe pulmonary hypertension. The + 139 ‘A’, adenine insertion variant in 5′UTR of edn1 gene has been reported to be associated with increased expression of Endothelin-1 in vitro. The aim of present study was to explore the association of this variant with the circulating levels of Endothelin-1 in vivo using archived DNA and plasma samples from 38 paediatric congenital heart disease (cyanotic and acyanotic) patients with severe pulmonary hypertension. Results The plasma Endothelin-1 levels were highly varied ranging from 1.63 to75.16 pg/ml. The + 139 ‘A’ insertion variant in 5′UTR of edn1 was seen in 8 out of 38 cases with only one acyanotic sample demonstrating homozygosity of inserted ‘A’ allele at + 139 site (4A/4A genotype). The plasma Endothelin-1 levels in children with homozygous variant 3A/3A genotype were comparable in cyanotic and acyanotic groups. Lone 4A/4A acyanotic sample had ET-1 levels similar to the median value of ET-1 associated with 3A/3A genotype and was absent in cyanotic group presumably due to deleterious higher ET-1 levels. The discussed observations, limited by the small sample size, are suggestive of homozygous adenine insertion variant posing a risk in cyanotic babies with Severe Pulmonary Hypertension.

Pulmonary artery hypertension (PAH) is a common and serious disease which is characterized by pulmonary vascular remodeling. Bosentan (BST) is the first approved oral targeted drug of endothelin-1 (ET-1) receptor antagonists for the treatment of PAH. MicroRNA-27a (miR-27a) and peroxisome proliferator-activated receptor γ (PPARγ) were found to be related to the pathogenesis of PAH. To further explore the signal transduction mechanism of BST in the treatment of PAH, we examined the effects of BST on endothelin receptors, miR-27a, and PPARγ. Meanwhile, the influence of miR-27a in the formation and development of PAH was discussed. Our results demonstrated that during the pathophysiology of PAH, miR-27a, PPARγ, and ET-1 were cross-inhibited, which indicated that the miR-27a/PPARγ/ET-1 signaling pathway was dysregulated; in addition, BST could competitively bind to ET-1 receptors and inhibit the miR-27a/PPARγ/ET-1 signaling pathway, thereby delaying the proliferation of PASMCs and affecting the development of PAH. Our results give a new understanding of the pathogenesis and treatment of PAH and provide more reliable evidence for the application of BST in the treatment of PAH in the clinic.

Objectives In obese adults the shape of the glucose response curve during an oral glucose tolerance test (OGTT) predicts future type 2 diabetes. Patients with an incessant increase or monophasic curves have increased risk compared to those with biphasic curves. Since type 2 diabetes is associated with increased cardiometabolic risk, we studied whether differences in OGTT response curve are associated with differences in cardiometabolic risk factors in healthy adolescents across a wide body mass index (BMI) range. Methods Sixty-nine (33F/36M), white adolescents (age: 15.2 ± 1.7 years; BMI: 21.5 ± 4.7 kg/m2; mean ± SD) were studied. Risk factors measured included percent body fat, blood pressure, lipids, augmentation index, reactive hyperemia, endothelin 1, plasminogen activator 1, inflammatory markers (interleukin 6, c-reactive protein), insulin secretion, insulin sensitivity (Matusda index), and disposition index (DI). Results Thirty-two subjects had biphasic responses; 35 subjects had monophasic responses and two females had incessant increases. Sex did not affect the frequency of responses. Glucose area under the curve during OGTT was greater in those with a mono vs. biphasic curves (p=0.01). Disposition index was markedly lower in subjects with a monophasic curve than in those with a biphasic curve (3.6 [2.3–5.0] vs. 5.8 [3.8–7.6], median [25th, 75th%] p=0.003). Triglyceride to high-density lipoprotein cholesterol (HDL) ratio was higher in subjects with a monophasic curve (p=0.046). Conclusions The decreased disposition index indicates that in healthy adolescents a monophasic response to OGTT is due to decreased insulin secretion relative to the degree of insulin resistance present. This was not associated with differences in most other cardiometabolic risk markers. Trial registration Clinical Trials.gov, NCT02821104.

Brain capillaries are crucial for cognitive functions by supplying oxygen and other nutrients to and removing metabolic wastes from the brain. Recent studies have demonstrated that constriction of brain capillaries is triggered by beta-amyloid (Aβ) oligomers via endothelin-1 (ET1)-mediated action on the ET1 receptor A (ETRA), potentially exacerbating Aβ plaque deposition, the primary pathophysiology of Alzheimer’s disease (AD). However, direct evidence is still lacking whether changes in brain capillaries are causally involved in the pathophysiology of AD. Using APP/PS1 mouse model of AD (AD mice) relative to age-matched negative littermates, we identified that reductions of density and diameter of hippocampal capillaries occurred from 4 to 7 months old while Aβ plaque deposition and spatial memory deficit developed at 7 months old. Notably, the injection of ET1 into the hippocampus induced early Aβ plaque deposition at 5 months old in AD mice. Conversely, treatment of ferulic acid against the ETRA to counteract the ET1-mediated vasoconstriction for 30 days prevented reductions of density and diameter of hippocampal capillaries as well as ameliorated Aβ plaque deposition and spatial memory deficit at 7 months old in AD mice. Thus, these data suggest that reductions of density and diameter of hippocampal capillaries are crucial for initiating Aβ plaque deposition and spatial memory deficit at the early stages, implicating the development of new therapies for halting or curing memory decline in AD. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-021-01024-7.

The aim of the study was to assess the efficacy and safety of taking tadalafil at a dose of 5 mg per day or 20 mg "on demand" for the state of endothelial function, the severity of erectile dysfunction (ERD) and urodynamics in men with mild to moderate ERD. Materials and methods The study included 60 male patients with benign prostatic hyperplasia aged 44 to 60 years with erectile dysfunction and cardiovascular pathology (arterial hypertension, ischemic heart disease). All patients were divided into 3 groups of 20 people. Patients of the 1st group for the treatment of ERD were prescribed tadalafil (Tadalafil SZ, NAO Severnaya Zvezda) in a daily dose of 5 mg / day. Men of the 2nd group took tadalafil 20 mg "on demand", but at least 1 time per week. The third group, in which tadalafil was not prescribed, served as a control. The duration of the study was 4 weeks. Results A significant effect of tadalafil on indicators of endothelial dysfunction (endothelin-1, nitric oxide, stiffness and reflection index, endothelial function indicator) was demonstrated. The use of tadalafil at a dose of 5 mg daily for four weeks has been shown to be advantageous compared to the use of 20 mg "on demand". Daily intake of tadalafil at a dose of 5 mg and 20 mg "on demand" was safe for patients with cardiovascular disease. Conclusion The data obtained make it possible to recommend this drug for the correction of endothelial dysfunction in patients with benign prostatic hyperplasia, including patients with concomitant cardiovascular diseases.

Li Feng,* Songhua Wang,* Feng Chen,* Cheng Zhang, Qiao Wang, Yuting Zhao, Zifeng Zhang School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zifeng Zhang 101 Shanghai Road, Xuzhou, Jiangsu Province, 221116, People’s Republic of ChinaTel + 86 516 83403729Email zhangzifengsuper@jsnu.edu.cnBackground: Emerging evidence from animal studies and clinical trials indicates that systemic inhibition of endothelin1 (ET1) signaling by endothelin receptor antagonists improves pathological features of diabetes and its complications. It is indicated that endothelin type A receptor (ETAR) plays a major role in ET1-mediated pathophysiological actions including diabetic pathology. However, the effects as well as the mechanistic targets of hepatic ET1/ETAR signaling inhibition on the pathology of metabolic diseases remain unclear. This study aimed to investigate the beneficial effects as well as the underlying mechanisms of hepatic ETAR knockdown on metabolism abnormalities in high-fat diet (HFD)-fed mice.Methods: Mice were fed a HFD to induce insulin resistance and metabolism abnormalities. L02 cells were treated with ET1 to assess the action of ET1/ETAR signaling in vitro. Liver-selective knockdown of ETAR was achieved by tail vein injection of adeno-associated virus 8 (AAV8). Systemic and peripheral metabolism abnormalities were determined in vivo and in vitro. Mitochondrial fragmentation was observed by transmission electron microscope (TEM) and mitoTracker red staining.Results: Here we provided in vivo and in vitro evidence to demonstrate that liver-selective knockdown of ETAR effectively ameliorated hepatic insulin resistance and hyperglycemia in HFD-fed mice. Mechanistically, hepatic ETAR knockdown alleviated mitochondrial fragmentation and dysfunction via inactivating 66-kDa Src homology 2 domain-containing protein (p66Shc) to recover mitochondrial dynamics, which was mediated by inhibiting protein kinase Cδ (PKCδ), in the livers of HFD-fed mice. Ultimately, hepatic ETAR knockdown attenuated mitochondria-derived oxidative stress and related liver injuries in HFD-fed mice. These ETAR knockdown-mediated actions were confirmed in ET1-treated L02 cells.Conclusion: This study defined an ameliorative role of hepatic ETAR knockdown in HFD-induced metabolism abnormalities by alleviating p66Shc-mediated mitochondrial fragmentation and consequent oxidative stress-related disorders and indicated that hepatic ETAR knockdown may be a promising therapeutic strategy for metabolic diseases.Keywords: endothelin-1, endothelin type A receptor, 66-kDa Src homology 2 domain-containing protein, mitochondrial fragmentation, metabolism abnormality

Aim To determine levels of markers for endothelial dysfunction and inflammation, endothelin-1, E-selectin, and tumor necrosis factor α (TNF-α) in patients with ischemic heart disease (IHD) and non-obstructive and obstructive coronary artery (CA) disease.Material and methods This study included 32 patients with verified IHD and non-obstructive (main group, n=19) and obstructive (comparison group, n=13) CA disease. Endothelial dysfunction was diagnosed by photoplethysmography and videocapillaroscopy. Serum concentrations of endothelin-1, E-selectin, and TNF- α were measured in all patients.Results Patients with non-obstructive CA disease showed a tendency towards more pronounced endothelial dysfunction (alternative stiffness index, 7.8 m /s [6.35; 9.08]; reflection index, 36.95 % [23.4; 52.65]; capillary density following reactive hyperemia, 54.33 cap /mm2 [48.92; 75.83]; capillary density following venous occlusion, 74.33 cap /mm2 [67.83; 93.00]) compared to the comparison group (alternative stiffness index, 9.05 m/s [7.08; 10.58]; reflection index, 28.25 % [23.35; 53.75]; capillary density following reactive hyperemia, 66.83 cap /mm2 [50.83; 78.67]; capillary density following venous occlusion, 87.0 cap /mm2 [77.58; 78.67]), although statistically significant differences were not found. Concentration of endothelin-1 was significantly higher in the IHD group with non-obstructive CA disease (0.45 ng/ml [0.28;0.65]) compared to patients with CA atherosclerotic stenosis (0.35 ng/ml [0.25; 0.38], p=0.035). Concentrations of E-selectin did not significantly differ between the groups (main group, 21.1 ng/ml [18.45; 35.03]; comparison group, 28.55 ng/ml [19.08; 35.01], p=0.29). In both groups, concentrations of TNF-α did not exceed the lower threshold of sensitivity (Conclusion Endothelial dysfunction and increased endothelin-1 in patients with non-obstructive CA disease along with inflammation may additionally contribute to the pathogenesis of IHD in the absence of hemodynamically significant CA stenoses. Too low level of TNFα in both groups prevented us from using it as a diagnostic marker. Further study is needed that would include a greater number of patients and a search for alternative markers.

Introduction: There is a bulk of literature data on the physiological roles of nitric oxide (NO) and endothelin- 1 (ET-1), but many facts remain unknown, especially in certain diseases such as peripheral arterial disease. Material and methods: This is an observational cross-sectional study. The subjects were patients diagnosed with PAD. Serum levels of NO and ET-1 were determined for all patients, and statistical data processing was performed according to the set goals. Results: The study included 64 patients with mean age 60.2 ± 12.7 years, mostly in stage II PAD according to Fontain (46.9%). Statistical analysis failed to determine a significant difference in serum NO or ET-1 values with respect to disease stage, sex, and body mass index (BMI). Certain oscillations were found in the mean values of NO related to smoking and diabetes but without statistical significance. There were also oscillations in the values of ET-1, with higher levels found in women, smokers and non-diabetics in whom this difference reached statistical significance (p = 0.041). Conclusion: Serum levels of NO and ET-1 in this study show some causal relationship with certain risk factors for PAD such as diabetes and smoking, but additional research is needed to fully understand their effects and interactions.

Objective: To investigate the effect of aspirin on pregnancy outcome and serum levels of endothelin-1 (ET-1) and thrombomodulin (TM) in pregnancy patients with chronic hypertension. Methods: Selected patients with chronic hypertension (mild to moderate) during pregnancy, who were enrolled and delivered in the Beijing Tongren Hospital Department of Obstetrics and Gynecology between January 1, 2019 and December 30, 2020. The patients were randomly divided into control group (60) and experimental group (60). The control group was treated with labetalol and the test group was treated with labetalol and aspirin. The therapeutic effect and pregnancy outcome of the two groups were compared. The serum levels of ET-1 and TM were measured before treatment and one week after treatment. Results: Systolic blood pressure (SBP) decreased significantly one week after treatment in the two groups (P Conclusion: Besides routine treatment, aspirin can improve the outcome of pregnant women with chronic hypertension, which may be related to the regulation of ET-1 and TM by aspirin.

Background Brain edema is one of the major causes of fatality and disability associated with injury and neurosurgical procedures. The goal of this study was to evaluate the effect of ulinastatin (UTI), a protease inhibitor, on astrocytes in a rat model of traumatic brain injury (TBI). Methodology A rat model of TBI was established. Animals were randomly divided into 2 groups – one group was treated with normal saline and the second group was treated with UTI (50,000 U/kg). The brain water content and permeability of the blood–brain barrier were assessed in the two groups along with a sham group (no TBI). Expression of the glial fibrillary acidic protein, endthelin-1 (ET-1), vascular endothelial growth factor (VEGF), and matrix metalloproteinase 9 (MMP-9) were measured by immunohistochemistry and western blot. Effect of UTI on ERK and PI3K/AKT signaling pathways was measured by western blot. Results UTI significantly decreased the brain water content and extravasation of the Evans blue dye. This attenuation was associated with decreased activation of the astrocytes and ET-1. UTI treatment decreased ERK and Akt activation and inhibited the expression of pro-inflammatory VEGF and MMP-9. Conclusion UTI can alleviate brain edema resulting from TBI by inhibiting astrocyte activation and ET-1 production.

Katarzyna Powierza,1 Jolanta Sawicka-Powierza,2 Beata Urban,3 Beata Żelazowska-Rutkowska,4 Bogdan Cylwik,4 Bożena Mikołuć,5 Olga Kowalewska,6 Alina Bakunowicz-Łazarczyk3 1University Clinical Hospital in Bialystok, Medical University of Bialystok, Bialystok 15-276, Poland; 2Department of Family Medicine, Medical University of Bialystok, Bialystok 15-054, Poland; 3Department of Pediatric Ophthalmology and Strabismus, Medical University of Bialystok, Bialystok 15-274, Poland; 4Department of Pediatric Laboratory Diagnostics, Medical University of Bialystok, Bialystok 15-274, Poland; 5Department of Pediatrics, Rheumatology, Immunology and Metabolic Bone Diseases, Medical University of Bialystok, Bialystok 15-274, Poland; 6Psychiatric Clinic, Lund, Division of Psychiatry, Lund 222 40, SwedenCorrespondence: Jolanta Sawicka-PowierzaDepartment of Family Medicine, Medical University of Bialystok, Mieszka I 4B Street, Bialystok 15-054, PolandTel +48 857326820Fax +48 857327848Email jolasawicka@gmail.comPurpose: The aim of our study was to determine endothelin-1 (ET-1) concentration in chronic idiopathic uveitis in children and adolescents depending on anatomical location and grade of inflammation.Methods: The cross-sectional study was conducted among 17 patients with chronic idiopathic uveitis and 22 healthy controls. Concentration of ET-1 in serum was determined using a commercially available ELISA kit. The concentration of C reactive protein (CRP) in serum was determined by immunoturbidimetric method using CRP4 reagent kit (Roche Diagnostics GmbH, Mannheim, Germany).Results: Statistically significant difference between ET-1 concentration in patients with chronic idiopathic uveitis and controls was found 1.33 (1.22; 1.48) vs 1.93 (1.1; 3.11), p = 0.008). No correlations were found between ET-1 concentration and age, either in chronic idiopathic uveitis patients or controls. Nine out of 17 patients presented with anterior uveitis, 5 with posterior and 3 with panuveitis. There were no differences in ET-1 concentration between anterior, posterior and panuveitis (p = 0.634), and in terms of grade of inflammation.Conclusion: ET-1 expression is disturbed in pediatric chronic idiopathic uveitis irrespective of the anatomical location and grade of inflammation. Lower expression of ET-1 plays a crucial role in disturbed vascular tone control and can result in permanent visual impairment in chronic non-infectious uveitis.Keywords: adolescents, children, chronic idiopathic uveitis, endothelin-1

Introduction: The involvement of the endothelial dysfunction (ED) in arterial hypotension (AHPT) post of spinal anesthesia (SA) has not been established. Objective: To determine if there is a relationship between ED and AHPT observed during the 1st 15 minutes after SA. Population and Methods: The study concerned 40 people who were to benefit from a programmed herniorrhaphy under SA and 40 controls (SA-). The correlations between mean plasma concentrations of endothelin-1 (CmET-1, pg/ml) and Vascular Cell Adhesion Molecule-1 (CmVCAM-1, pg/ml) taken from SA+ one hour before (H0), then 15 minutes after the SA (H15) and the mean arterial pression (AMP, mmHg) with heart rate (bpm) were analyzed (p - were 1.07 and 3.34, respectively, compared to 1.12 (p = 0.735) and 3.57 (p = 0.862) in SA+ at H0 and H15. In SA+, at H15, CmET-1 was 1.13 (p = 0.823) and CmVCAM-1 was 3.57 (p = 0.257). In SA-, a negative correlation existed between CmET-1 and CmVCAM-1 (r = -0.438; p = 0.005). Conversely, in SA+, whether at H0 (r = -0.31; p = 0.051) or at H15 (r = 0.024; p = 0.883), no correlation existed between CmET-1 and CmVCAM-1, nor between MAP and ED markers (r = 0.111; p = 0.325). Conclusion: These results show that there is no relationship between the AHPT which occurs during the first fifteen minutes post SA, CmVCAM-1 and CmET-1. Moreover, these data suggest that ED is not involved in AHPT post SA.

Endothelial dysfunction is considered one of the main mechanisms for the further development of arterial hypertension (AH) and its complications, and endothelin-1 (ЕТ-1) plays one of the key roles in this process. Endothelium is drawn into the pathological process at the earliest stages of AH development. ЕТ-1 is currently considered as a marker and predictor of the stage and consequences of AH, chronic heart failure (CHF), coronary heart disease (CHD), in particularly, acute myocardial infarction (MI), heart rhythm disorders, pulmonary hypertension, atherosclerotic vascular injury, target vascular disorders. One factor that may influence the level of ЕТ-1 is the endothelin-1 gene Lys198Asn polymorphism, which is considered by many researchers as a possible genetic marker of AH. However, the effect of this polymorphism on the level of plasma ЕТ-1 level in patients with AH of varying severity in Ukraine is understudied. The basis of this work were the materials of a complete examination of 160 patients with a verified diagnosis of AH I, stage II of 1, 2, 3 degrees (main group) and 110 apparently healthy persons (control group). Patients of the main group were divided into three subgroups: 1st group ­– 75 patients with normal body weight; 2nd group – 48 overweight patients; 3rd group – 37 patients with alimentary obesity. In obese patients, the waist circumference in women was around 103 (96–115) cm, and in men – 108 (105–116) cm, which indicates an abdominal type of obesity in these patients. As a result of the study, it was found that the level of ЕТ-1 is higher in patients with AH who suffer with overweight and obesity as compared with patients with AH and normal body weight. Also, the peptide level depends on the genotype of patients and is higher in AH patients with the genotype Asn198Asn and Lys198Asn as compared to carriers of the genotype Lys198Lys.

OBJECTIVE The aim: Is to determine the levels of markers of endothelial dysfunction in young men with myocardial infarction and their changes during the treatment with beta-blockers with different pharmacological properties. PATIENTS AND METHODS Materials and methods: 112 male patients of Caucasian race of the Ukrainian population under the age of 50 with MI. Group I received Nebivolol, group II - bisoprolol. RESULTS Results: During the 6-month follow-up, positive dynamics of NOS-2 and ET-1 was observed. The level of NOS-2 in groups I - II was 4272.3±162.7, 4629.7±161.2 pg/mL, respectively (p

본 연구는 만 65~75세 제2형 당뇨 여성노인을 대상으로 12주간의 걷기와 탄력밴드 운동 프로그램이 혈중지질, 엔도텔린-1 및 혈관내피성장인자에 미치는 영향을 구명하기 위하여 복합운동군 14명, 대조군 13명으로 구분하여 실시하였다. 걷기와 탄력밴드 운동은 주 2회, 회당 60분으로 구성하였고, 2019년 5월부터 8월에 걸쳐 실시되었다. 걷기운동은 1-4주는 최대여유심박수의 40-50%, 5-8주는 50-60%, 9-12주는 60-70%의 강도로 실시하였고, 탄력밴드 운동은 1-4주 12회/1세트, 5-8주 12회/2세트, 9-12주 15회/2세트로 점증적으로 강도를 증가하였다. 운동 전·후의 항목별 상호작용 효과 검증을 위해 이원배치 반복측정 분산분석을 실시하였으며, 상호작용효과 검증을 위해 시기 간 대응표본 t검정, 집단 간 독립표본 t검정, 각 항목별 유의수준은 .05로 설정하여 분석하였다. 그 결과 중성지방(p=.019), 엔도텔린-1(p=.002)에서 상호작용 효과가 나타났고, 운동군의 중성지방 감소(p=.028)와 고밀도 지단백 콜레스테롤이 증가(p=.008)하였다. 운동군의 엔도텔린-1(p=.085) 및 혈관내피성장인자(p=.613)에서는 유의한 차이가 없었으나, 대조군의 엔도텔린-1(p

Introduction . Diabetes mellitus is one of the most common diseases in the world. In 4–25 % of patients with this pathology, diabetic foot syndrome develops, leading to a large number of amputations accompanied by postoperative mortality. Aim . To assess the relationship of polymorphisms of the VEGFA 634 C˃G and MMP9 8202 A˃G genes with markers of endothelial dysfunction and state of the microvasculature in diabetes mellitus. Materials and methods . In 198 people with uncomplicated diabetes mellitus and 199 people with diabetic feet, polymorphisms 634 C˃G of the VEGFA gene and 8202 A˃G of the MMP9 gene were studied by polymerase chain reaction. The content of endothelin 1, NO 2 and NO 2 – /NO 3 – , MMP 9 and state of microcirculation at three points were studied by laser Doppler flowmetry in 30 people from each group, comparable in frequency of the indicated gene polymorphisms. Results . The frequency of polymorphisms of genes VEGFA 634 C˃G, MMP9 8202 A>G did not differ in the groups of patients. In diabetic feet, a decrease in the total perfusion index by 1.4, 1.8 and 1.5 times was recorded at three points. At a point on the forearm with a diabetic foot, a 1.6-fold decrease in the temporal variability of perfusion was revealed; at the dorsum and first toe of the foot, a decrease in the coefficient of variation by 1.7 and 1.5 times was revealed. In patients with different variants of the course of diabetes mellitus, there were no differences in the levels of endothelin-1, NO 2 and NO 2 – / NO 3 – , MMP 9. Conclusion . Polymorphisms of the VEGFA 634 C˃G, MMP9 8202 A˃G genes in different variants of the course of3 – diabetes mellitus correlate with indicators of general state of the microvasculature. The parallelism of changes in the content of endothelin 1, MMP 9 and polymorphic variants of the MMP9 8202 A˃G gene indicates a deep remodeling of the vasculature, which may be an important link in the pathogenesis of the development of complications of diabetes mellitus.

Background: Vascular endothelial cells play an important role in regulating vascular activity by producing vascular active substances such as endothelin-1 and nitric oxide. The aim of this study was to investigate the effect of eight weeks of water resistance training with dark chocolate consumption on plasma levels of endothelin-1, nitric oxide and quality of life in elderly women. Materials and Methods: In this semi-experimental study, 37 elderly women (mean ± standard deviation; age, 65.6 ± 3.1 years; weight 75.71 ± 7.7 kg) were purposefully divided into four complementary groups. Supplementation and exercise, exercise and control were included. The training protocol was performed for eight weeks of water resistance training. Supplementation of 30 grams of 83% dark chocolate daily was used for 8 weeks. Quality of life index was measured by SF-36 evaluation and plasma endolin-1 levels by ELISA and serum nitrite levels as the main metabolite of NO. One-way analysis of variance and Bonferroni’s post hoc test were used for statistical analysis. Results: The results showed that the mean quality of life index in the water resistance training group was significantly higher than the control group in elderly women (p = 0.036). Also, the mean NO levels in the combined group were significantly higher than the control group (p = 0.001). But the mean levels of endothelin-1 in the combined group were significantly lower than the control group (p = 0.012). Conclusion: Based on the present results, it can be concluded that resistance training in water along with consumption of dark chocolate may reduce endothelin-1 levels and increase NO levels to improve endothelial function and increase quality of life in elderly women. Keywords: Dark chocolate, Water resistance training, Endothelial, Quality of life, Elderly.

Objectives Endothelin-1 (ET-1) has been implicated in the pathogenesis of inflammatory and fibrotic diseases, including systemic sclerosis. In addition to modulating vascular tone and extracellular matrix turnover, ET-1 up-regulates cell surface adhesion molecules–intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1).The aim of the study was to evaluate the diagnostic value of the detection of ET-1, VCAM-1 and ICAM-1 in the diagnosis of systemic sclerosis. Methods A total of 30 patients with systemic sclerosis from Vilnius University Hospital Santaros Clinics were included in the study. Serum levels of ICAM-1, VCAM-1 and ET-1 were assessed by enzyme immunoassay. Results ET-1 concentration was associated with VCAM-1 concentration (r=0.687; p Conclusions The results of this study indicated that ET-1 and VCAM-1 may be assessed together as markers of inflammation and the identification of patients at high risk for disease progression.

Objective. To study the state of endothelial function in children with familial hypercholesterolemia by evaluating the flow-dependent vasodilation of the brachial artery and serum nitric oxide and endothelin-1 levels. Children characteristics and research methods . The study included total 62 children: 30 children (mean age 10,3 years ± 2,8) with a heterozygous form of familial hypercholesterolemia, not taking lipid-lowering therapy (main group), and 32 healthy children (mean age 10,3 years ± 2,8) in the control group. The content of endothelin-1 and nitric oxide in blood serum were determined by enzyme immunoassay. Flow-dependent vasodilation of brachial artery was measured using Philips Affinity 70 (Release 3,0.3, Philips Healthcare, USA). Results. The analysis of endothelin-1 level did not reveal statistically significant differences between healthy children and patients with familial hypercholesterolemia (0,213 [0,012; 0,368] and 0,227 [0,15; 0,315] pmol/l accordingly; p=0,062). The level of nitrogen oxide in healthy children was 33,6 [20—51] pmol/l, while patients with familial hypercholesterolemia had statistically significantly higher level of nitrogen oxide — 103,7 [48—152] pmol/l, p=0,001). Flow-dependent brachial artery vasodilation in healthy children was 9,82 [7,8; 11,2]% and in patients with familial hypercholesterolemia this indicator was decreased — 9,46 [6,5; 10,8]% (p=0,742). Conclusion. A study of endothelial function in children with familial hypercholesterolemia aged 7—11 years revealed an increase in the concentration of nitrogen oxide relative to healthy patients, probably of a compensatory nature. The flow-dependent vasodilation of the brachial artery and the level of endothelin-1 did not significantly differ from the control group. Due to possible cumulative effect of low-density proteins, it is necessary to monitor endothelial function in children with familial hypercholesterolemia in dynamics.

Sickness syndrome is an adaptive response that can be distinguished by specific signs and symptoms, such as fever and generalized hyperalgesia. Endothelin-1 (ET-1) is produced by inflammatory stimuli, including lipopolysaccharide, and involved in the pathogenesis of inflammation and pain by acting through ETA and ETB receptors. ET-1 also induces fever by acting on the central nervous system. The present study investigated the role of ET-1 in sickness syndrome responses, including hyperalgesia, anhedonia, and hypolocomotion. Intracerebroventricular ET-1 administration induced mechanical and thermal hyperalgesia in rats, which was ameliorated by the ETA receptor antagonist BQ123 and exacerbated by the ETB receptor antagonist BQ788. A cyclooxygenase blocker did not alter hyperalgesia that was induced by ET-1. Lipopolysaccharide administration induced hyperalgesia, and both BQ123 and BQ788 abolished this mechanical hyperalgesia, but the thermal response was only partially blocked. The blockade of ETA receptors in the hypothalamus also abolished lipopolysaccharide-induced mechanical hyperalgesia, and the ETB receptor antagonist did not influence this response. Lipopolysaccharide also induced anhedonia, reflected by lower sucrose preference, and reduced locomotor activity. Both antagonists restored locomotor activity, but only BQ788 reversed the reduction of sucrose preference. These results indicate that ET-1 and both ETA and ETB receptors are involved in various responses that are related to sickness syndrome, including hyperalgesia, anhedonia, and hypolocomotion, that is induced by LPS. Hypothalamic ETA but not ETB receptors are involved in mechanical hyperalgesia that is observed during lipopolysaccharide-induced sickness syndrome.

Cardiac ANP (atrial natriuretic peptide) moderates arterial blood pressure. The mechanisms mediating its hypotensive effects are complex and involve inhibition of the renin-angiotensin-aldosterone system, increased natriuresis, endothelial permeability, and vasodilatation. The contribution of the direct vasodilating effects of ANP to blood pressure homeostasis is controversial because variable levels of the ANP receptor, GC-A (guanylyl cyclase-A), are expressed among vascular beds. Here, we show that ANP stimulates GC-A/cyclic GMP signaling in cultured microvascular pericytes and thereby the phosphorylation of the regulatory subunit of myosin phosphatase 1 by cGMP-dependent protein kinase I. Moreover, ANP prevents the calcium and contractile responses of pericytes to endothelin-1 as well as microvascular constrictions. In mice with conditional inactivation (knock-out) of GC-A in microcirculatory pericytes, such vasodilating effects of ANP on precapillary arterioles and capillaries were fully abolished. Concordantly, these mice have increased blood pressure despite preserved renal excretory function. Furthermore, acute intravascular volume expansion, which caused release of cardiac ANP, did not affect blood pressure of control mice but provoked hypertensive reactions in pericyte GC-A knock-out littermates. We conclude that GC-A/cGMP–dependent modulation of pericytes and microcirculatory tone contributes to the acute and chronic moderation of arterial blood pressure by ANP. Graphic Abstract A graphic abstract is available for this article.

Preeclampsia (PE) is characterized by new onset hypertension in association with elevated soluble fms-like tyrosine kinase-1 (sFlt-1) and preproendothelin-1 (PPET-1) levels. Currently there is no effective treatment for PE except for early delivery of the fetal placental unit, making PE a leading cause for premature births worldwide. Administration of 17-hydroxyprogesterone caproate (17-OHPC) is used for prevention of recurrent preterm birth. This study was designed to test the hypothesis that 17-OHPC improves hypertension and ET-1 in response to elevated sFlt-1 in pregnant rats. sFlt-1 was infused into normal pregnant (NP) Sprague-Dawley rats (3.7 μg·kg−1·day−1 for 6 days, gestation days 13–19) in the presence or absence of 17-OHPC (3.32 mg/kg) administered via intraperitoneal injection on gestational days 15 and 18. Mean arterial blood pressure (MAP), pup and placenta weights, renal cortex PPET-1 mRNA levels and nitrate-nitrite levels were measured on GD 19. Infusion of sFlt-1 into NP rats elevated mean arterial pressure (MAP) compared with control NP rats: 115 ± 1 (n = 13) vs. 99 ± 2 mmHg (n = 12, p

Enhanced vasoconstriction is increasingly identified as an important contributor to the development of pulmonary hypertension. Chronic hypoxia results in enhanced Rho kinase mediated Ca 2+ sensitization contributing to pressure-dependent pulmonary arterial tone as well as augmented vasoconstriction to endothelin-1 and depolarizing stimuli. We sought to investigate the interaction between these vasoconstrictor stimuli in isolated, pressurized, pulmonary arteries. We used the K + ionophore, valinomycin, to clamp membrane potential (V m ) to investigate the role of membrane depolarization in endothelin-1 and pressure-dependent constriction, and endothelin-1 receptor inhibitors to determine whether membrane depolarization or stretch signal through endothelin-1 receptors. Clamping V m prevented pressure-dependent tone, but not enhanced vasoconstriction to endothelin-1 following chronic hypoxia. Furthermore, endothelin-1 receptor inhibition had no effect on either pressure-dependent tone or vasoconstriction to KCl. As Src kinases contribute to both pressure-dependent tone and enhanced endothelin-1 vasoconstriction following chronic hypoxia, we further investigated their role in depolarization-induced vasoconstriction. Inhibition of Src kinases attenuated enhanced vasoconstriction to KCl. We conclude that membrane depolarization contributes to pressure-dependent tone but not enhanced vasoconstriction to ET-1, and that Src kinases serve as upstream mediators facilitating enhanced Rho kinase-dependent vasoconstriction following chronic hypoxia.

Objectives It is known that the receptor for advanced glycation end products (RAGE) activation is involved in the pathogenesis of cardiovascular disease in diabetes. Previous studies have shown the presence of angiotensin II (Ang II) in diabetes, suggesting a role for this hormone during the disease. However, the association between RAGE and Ang II during pathologic cardiac remodelling after streptozotocin (STZ)-induced diabetes remains unclear. Because Ang II is capable of inducing pro-inflammatory events, blocking its production (enalapril), and its action on its receptor (losartan) could decrease inflammatory events in the myocardium in this experimental model of diabetes. Thus, the aim of this study was to assess the association between RAGE expression, inflammatory events and Ang II in the myocardium during STZ-induced diabetes. Methods Diabetes was induced by intravenous injection of STZ in Sprague-Dawley rats. Myocardial expressions of RAGE, monocyte/macrophage (ED-1–positive cells) infiltration and the intercellular adhesion molecule-1 were determined by histochemical methods. Levels of circulating endothelin-1 (ET-1) were determined by enzyme-linked immunoassay. Effects of Ang II included blocking using losartan (15 mg/kg body weight per day by gastric gavage) or enalapril (18 mg/kg body weight per day by gastric gavage). Results Increased expression of both RAGE and ED-1 was seen in the myocardium, but expression of myocardial vascular intercellular adhesion molecule-1 remained unchanged. Circulating levels of ET-1 in STZ rats were increased. Renin‒angiotensin system inhibition decreased expression of myocardial RAGE, ED-1 and ET-1. Conclusions The present findings suggest a role for Ang II in myocardial inflammation in STZ-induced diabetes mediated by RAGE and ET-1.

Sex differences in the immune response can also affect the febrile response, particularly the fever induced by lipopolysaccharide (LPS). However, other pathogen-associated molecular patterns, such as zymosan A (Zym) and polyinosinic-polycytidylic acid (Poly I:C), also induce fever in male rats with a different time course of cytokine release and different mediators such as endothelin-1 (ET-1). This study investigated whether female sex hormones affect Zym- and Poly I:C-induced fever and the involvement of ET-1 in this response. The fever that was induced by Zym and Poly I:C was higher in ovariectomized (OVX) female rats compared with sham-operated female rats. Estrogen replacement in OVX females reduced Zym- and Poly I:C-induced fever. The ETB receptor antagonist BQ788 reversed the LPS-induced fever in cycling females but not in OVX females. BQ788 did not alter the fever that was induced by Zym or Poly I:C in either cycling or OVX females. These findings suggest that the febrile response in cycling females is lower, independently of the stimulus that is inducing it and is probably controlled by estrogen. Also, ET-1 seems to participate in the febrile response that was induced by LPS in males and cycling females but not in the LPS-induced fever in OVX females. Additionally, ET-1 was not involved in the febrile response that was induced by Zym or Poly I:C in females.

Background: Cardiac hypertrophic growth is mediated by robust changes in gene expression and changes that underlie the increase in cardiomyocyte size. The former is regulated by RNA polymerase II (pol II) de novo recruitment or loss; the latter involves incremental increases in the transcriptional elongation activity of pol II that is preassembled at the transcription start site. The differential regulation of these distinct processes by transcription factors remains unknown. Forkhead box protein O1 (FoxO1) is an insulin-sensitive transcription factor that is also regulated by hypertrophic stimuli in the heart. However, the scope of its gene regulation remains unexplored. Methods: To address this, we performed FoxO1 chromatin immunoprecipitation–deep sequencing in mouse hearts after 7 days of isoproterenol injections (3 mg·kg −1 ·mg −1 ), transverse aortic constriction, or vehicle injection/sham surgery. Results: Our data demonstrate increases in FoxO1 chromatin binding during cardiac hypertrophic growth, which positively correlate with extent of hypertrophy. To assess the role of FoxO1 on pol II dynamics and gene expression, the FoxO1 chromatin immunoprecipitation–deep sequencing results were aligned with those of pol II chromatin immunoprecipitation–deep sequencing across the chromosomal coordinates of sham- or transverse aortic constriction–operated mouse hearts. This uncovered that FoxO1 binds to the promoters of 60% of cardiac-expressed genes at baseline and 91% after transverse aortic constriction. FoxO1 binding is increased in genes regulated by pol II de novo recruitment, loss, or pause-release. In vitro, endothelin-1– and, in vivo, pressure overload–induced cardiomyocyte hypertrophic growth is prevented with FoxO1 knockdown or deletion, which was accompanied by reductions in inducible genes, including Comtd1 in vitro and Fstl1 and Uck2 in vivo. Conclusions: Together, our data suggest that FoxO1 may mediate cardiac hypertrophic growth via regulation of pol II de novo recruitment and pause-release; the latter represents the majority (59%) of FoxO1-bound, pol II–regulated genes after pressure overload. These findings demonstrate the breadth of transcriptional regulation by FoxO1 during cardiac hypertrophy, information that is essential for its therapeutic targeting.

This study aims to explore the changes in endothelin-1 (ET-1), plasma neuropeptide Y, and calcitonin gene–related peptide (CGRP) in child patients before and after operation. A total of 80 child patients with congenital heart disease (CHD) complicated with pulmonary hypertension (PH) were enrolled and divided into control group (n = 40, conservative treatment for various reasons) and observation group (n = 40, active preoperative preparation and timely operative intervention) according to different treatments. There were positive correlations between systolic pulmonary arterial pressure (sPAP) and ET-1, plasma neuropeptide Y, while negative correlation between sPAP and CGRP. In conclusion, our data demonstrate that the levels of ET-1, plasma neuropeptide Y, and CGRP in PH-CHD were significantly changed after interventions, which provides new leads as alternative biomarkers to assess the efficacy of treatments against PH-CHD.

Portal hypertension is one of the most important cirrhosis-associated complications of chronic liver disease, leading to significant morbidity and mortality. After chronic liver injury, hepatic stellate cells reside in the perisinusoidal space activted and acquire a myofibroblast-like phenotype. The activated hepatic stellate cells act as both sources as well as the target for a potent vasoconstrictor endothelin-1. Activation of hepatic stellate cells plays a vital role in the onset of cirrhosis by way of increased extracellular matrix production and the enhanced contractile response to vasoactive mediators such as endothelin-1. In fibrotic/cirrhotic liver, activated hepatic stellate cells produce endothelin-1 leading to an imbalance between pro and antifibrotic factors responsible for enormous extracellular matrix synthesis. Thus, extracellular matrix deposition in the perisinusoidal space further augments liver stiffness and elevates the vascular tone and portal hypertension. Portal hypertension is a complex process modulated by several cell types like hepatic stellate cells, liver sinusoidal endothelial cells, Kupffer cells, injured hepatocytes, immune cells, and biliary epithelial cells. Therefore, targeting a single cell type may not be useful for regression of cirrhosis and portal hypertension. Nevertheless, numerous findings indicate that functionally liver sinusoidal endothelial cells and hepatic stellate cells closely regulate the sinusoidal blood flow via synthesis of several vasoactive molecules including endothelin-1, and hence targeting these cells with novel pharmacological agents may offer promising results. Impact statement Portal hypertension is pathologically defined as increase of portal venous pressure, mainly due to chronic liver diseases such as fibrosis and cirrhosis. In fibrotic liver, activated hepatic stellate cells increase their contraction in response to endothelin-1 (ET-1) via autocrine and paracrine stimulation from liver sinusoidal endothelial cells and injured hepatocytes. Clinical studies are limited with ET receptor antagonists in cirrhotic patients with portal hypertension. Hence, studies are needed to find molecules that block ET-1 synthesis. Accumulation of extracellular matrix proteins in the perisinusoidal space, tissue contraction, and alteration in blood flow are prominent during portal hypertension. Therefore, novel matrix modulators should be tested experimentally as well as in clinical studies. Specifically, tumor necrosis factor-α, transforming growth factor-β1, Wnt, Notch, rho-associated protein kinase 1 signaling antagonists, and peroxisome proliferator-activated receptor α and γ, interferon-γ and sirtuin 1 agonists should be tested elaborately against cirrhosis patients with portal hypertension.

Background Quercetin 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. Methods The 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. Results In 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. Conclusion Quercetin attenuates RUPP induced hypertension in pregnant rats through the regulation of ET-1 and ETAR.

The endothelin system has an important role in bone modelling during orthodontic tooth movement (OTM); however, little is known about the involvement of endothelin B receptors (ETB) in this process. The aim of this study was to evaluate the role of ETB in bone modelling during OTM using ETB knockout rats (ETB-KO). Thirty-two male rats were divided into 4 groups (n = 8 per group): the ETB-KO appliance group, ETB-KO control group, wild type (ETB-WT) appliance group, and ETB-WT control group. The appliance consisted of a super-elastic closed-coil spring placed between the first and second left maxillary molar and the incisors. Tooth movement was measured on days 0 and 35, and maxillary alveolar bone volume, osteoblast, and osteoclast volume were determined histomorphometrically on day 35 of OTM. Next, we determined the serum endothelin 1 (ET-1) level and gene expression levels of the osteoclast activity marker cathepsin K and osteoblast activity markers osteocalcin and dentin matrix acidic phosphoprotein 1 (DMP1) on day 35. The ETB-KO appliance group showed significantly lower osteoblast activity, diminished alveolar bone volume and less OTM than the ETB-WT appliance group. Our results showed that ETB is involved in bone modelling in the late stage of OTM.

Neutralization of FasL is linked to suppression of hypertension, placental inflammation, and endothelin system activation in an animal model of hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. During HELLP syndrome the placenta has been reported to serve as the primary source of Fas ligand (FasL), which has an impact on inflammation and hypertension during pregnancy and is dysregulated in women with severe preeclampsia and HELLP syndrome. We hypothesize that neutralization of FasL during pregnancy in an animal model of HELLP syndrome decreases inflammation and placental apoptosis, improves endothelial damage, and improves hypertension. On gestational day (GD) 12, rats were chronically infused with placental antiangiogenic factors sFlt-1 and sEng to induce HELLP syndrome. To neutralize FasL, MFL4 or FasL antibody was infused into a subset of HELLP or normal pregnant rats on GD13. IgG infusion into another group of NP and HELLP rats on GD13 was used as a control for FasL antibody, and all rats were euthanized on GD19 after blood pressure measurement. Plasma and placentas were collected to assess inflammation, apoptosis, and the degree of placental debris activation of endothelial cells. Administration of MFL4 to HELLP rats significantly decreased blood pressure compared with untreated HELLP rats and HELLP rats infused with IgG and improved the biochemistry of HELLP syndrome. Both circulating and placental FasL were significantly attenuated in response to MFL4 infusion, as were levels of placental and circulating TNFα when compared with untreated HELLP rats and HELLP rats infused with IgG. Endothelial cells exposed to placental debris and media from HP + MFL4 rats secreted significantly less endothelin-1 compared with stimulated endothelial cells from HELLP placentas. Neutralization of FasL is associated with decreased MAP and improvement in placental inflammation and endothelial damage in an animal model of HELLP syndrome.