Elevated Endothelin-1 Research Articles

Combined hydroxyurea and ETA receptor blockade reduces renal injury in the humanized sickle cell mouse.

The objective of this study is to determine if ambrisentan (ETA selective antagonist) and hydroxyurea (HU) treatment has a synergistic effect on renal injury in sickle cell nephropathy when compared to HU treatment alone. The premise of the study is based on recent studies showing that endothelin-1 (ET-1) contributes to the pathophysiology of nephropathy in sickle cell disease (SCD) and that ETA receptor blockade improves renal function and protects against renal injury. Hydroxyurea (HU) is commonly prescribed for the treatment of SCD and has been shown to reduce renal injury in patients with SCD. Male 12-week-old humanized sickle mice (HbSS) and their genetic controls (HbAA) were treated with vehicle, HU, ambrisentan, or HU with ambrisentan for 2weeks and renal structure and function were assessed. Vehicle treated HbSS mice exhibited significant proteinuria compared to vehicle treated HbAA mice. HbSS mice also displayed significantly elevated plasma ET-1 concentrations and decreased urine osmolality compared to HbAA controls. Proteinuria was significantly lower in both HU and ambrisentan treated animals compared to vehicle treated HbSS mice; however, there was no additional improvement in HbSS mice treated with combined ambrisentan and HU. The combination of HU and ambrisentan resulted in significantly lower KIM-1 excretion, glomerular injury, and interstitial inflammation than HU alone. These findings indicate that HU and ETA receptor blockade produce similar reductions in renal injury in the humanized sickle mouse suggesting that both treatments may converge on the same mechanistic pathway.

Clinical Characteristics and Long-Term Outcomes of Patients with Combined Post and Precapillary Hypertension in HFpEF

Background The prevalence of pulmonary hypertension (PH) in HFpEF is gradually increasing. Patients with pulmonary venous hypertension due to left heart disease who develop superimposed pulmonary vascular disease are diagnosed to have HFpEF with combined post and precapillary hypertension (HFpEF-CPH). In this study we aim to investigate this subset of PH and look at clinical characteristics, biomarkers which may play a part in etiology and long-term clinical outcomes. Methods Single center prospective cohort study including 60 patients (30 control patients and 30 patients with HFpEF-CPH) who underwent right heart catherization and had Endothelin 1, Big Endothelin 1 and Neprilysin samples collected from the wedge position. They were followed for a year for hospital admission and two years for mortality. Results HFpEF-CPH patients had an average age of 53±20 years with majority being female 74% (n=22), 86% were hypertensive (n=25), 55% had Diabetes (n=16), 38% had coronary artery disease (n=11) and 51% were smoker (n=15). Patients with HFpEF-CPH were found to have elevated Endothelin 1 levels compared to control (2.5±1 pg/mL versus 1.5±1 pg/mL, p=0.00), however, no significant difference in the levels of Big Endothelin1 and Neprilysin were found between the two groups. Compared to the control group, patients with HFpEF-CPH had increased one-year hospitalization (p=0.02), increased one-year repeated hospital admissions (p=0.01) and increased mortality within the two year follow up period (p=0.03). Conclusion Increased Endothelin 1 levels observed in patients with HFpEF-CPH suggest a possible role in the etiology of this disease process and a potential target for pharmacological antagonism. Moreover, patients with HFpEF-CPH were found to have poor long-term outcomes and need to be monitored closely.

Blockade of Endothelin-1 Receptor Type B Ameliorates Glucose Intolerance and Insulin Resistance in a Mouse Model of Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is associated with insulin resistance (IR) and glucose intolerance. Elevated endothelin-1 (ET-1) levels have been observed in OSA patients and in mice exposed to intermittent hypoxia (IH). We examined whether pharmacological blockade of type A and type B ET-1 receptors (ETA and ETB) would ameliorate glucose intolerance and IR in mice exposed to IH. Subcutaneously implanted pumps delivered BQ-123 (ETA antagonist; 200 nmol/kg/day), BQ-788 (ETB antagonist; 200 nmol/kg/day) or vehicle (saline or propyleneglycol [PG]) for 14 days in C57BL6/J mice (10/group). During treatment, mice were exposed to IH (decreasing the FiO2 from 20.9% to 6%, 60/h) or intermittent air (IA). After IH or IA exposure, insulin (0.5 IU/kg) or glucose (1 mg/kg) was injected intraperitoneally and plasma glucose determined after injection and area under glucose curve (AUC) was calculated. Fourteen-day IH increased fasting glucose levels (122 ± 7 vs. 157 ± 8 mg/dL, PG: 118 ± 6 vs. 139 ± 8; both p < 0.05) and impaired glucose tolerance (AUCglucose: 19,249 ± 1105 vs. 29,124 ± 1444, PG AUCglucose: 18,066 ± 947 vs. 25,135 ± 797; both p < 0.05) in vehicle-treated animals. IH-induced impairments in glucose tolerance were partially ameliorated with BQ-788 treatment (AUCglucose: 21,969 ± 662; p < 0.05). Fourteen-day IH also induced IR (AUCglucose: 7185 ± 401 vs. 8699 ± 401; p < 0.05). Treatment with BQ-788 decreased IR under IA (AUCglucose: 5281 ± 401, p < 0.05) and reduced worsening of IR with IH (AUCglucose: 7302 ± 401, p < 0.05). There was no effect of BQ-123 on IH-induced impairments in glucose tolerance or IR. Our results suggest that ET-1 plays a role in IH-induced impairments in glucose homeostasis.

3,7-Bis(2-hydroxyethyl)icaritin, a potent inhibitor of phosphodiesterase-5, prevents monocrotaline-induced pulmonary arterial hypertension via NO/cGMP activation in rats

Pulmonary arterial hypertension (PAH) is a chronic progressive disease which leads to elevated pulmonary arterial pressure and right heart failure. 3,7-Bis(2-hydroxyethyl)icaritin (ICT), an icariin derivatives, was reported to have potent inhibitory activity on phosphodiesterase type 5 (PDE5) which plays a crucial role in the pathogenesis of PAH. The present study was designed to investigate the effects of ICT on monocrotaline (MCT)-induced PAH rat model and reveal the underlying mechanism. MCT-induced PAH rat models were established with intragastric administration of ICT (10, 20, 40 mg/kg/d), Icariin (ICA) (40 mg/kg/d) and Sildenafil (25 mg/kg/d). The mean pulmonary arterial pressure (mPAP) and right ventricle hypertrophy index (RVHI) were measured. Pulmonary artery remodeling was assessed by H&E staining. Blood and lung tissue were collected to evaluate the level of endothelin 1 (ET-1), nitric oxide (NO), and cyclic guanosine monophosphate (cGMP). The expressions endothelial nitric oxide synthase (eNOS) and PDE5A in lung tissues were determined by Western blot analysis. The results showed that ICT reduced RVHI and mPAP, and reversed lung vascular remodeling in rats with MCT-induced PAH. ICT also reversed MCT-induced ET-1 elevation, NO and cGMP reduction in serum or lung tissue. Moreover, ICT administration significantly induced eNOS activation and PDE5A inhibition. ICT with lower dose had better effects than ICA. In summary, ICT is more effective in preventing MCT-induced PAH in rats via NO/cGMP activation compared with ICA. These findings demonstrate a novel mechanism of the action of ICT that may have value in prevention of PAH.

Early life stress induces endothelial‐derived HDAC9 and ET‐1 expression

Exposure to adverse childhood experiences, also known as early life stress (ELS), is an independent risk factor for the development of cardiovascular disease (CVD) in adulthood. Endothelial dysfunction is a major contributor to the development of CVD and has been linked to childhood adversity induced CVD risk. We previously reported circulating ET‐1 levels are significantly elevated in young adults exposed to childhood adversity in humans. Endothelin‐1 (ET‐1) via the ETA receptor promotes endothelial dysfunction and vascular inflammation. However, the regulation of ET‐1 by ELS and the mechanistic link between elevated ET‐1 levels and ELS‐induced increase in CVD risk remains unknown. In a mouse model of ELS involving maternal separation and early weaning (MSEW), we previously reported that ELS induced elevated plasma ET‐1 as well as increased vascular histone deacetylase 9 (HDAC9) protein expression with no changes in expression of other HDAC isoforms. Moreover, MSEW mice develop endothelial dysfunction in adulthood that is attenuated by a pan‐inhibitor of Class I and class II HDAC proteins, trichostatin A (TSA). HDACs are a family of epigenetic enzymes that regulate transcription through deacetylation of histone and non‐histone proteins. In humans, previous studies have shown SNPs in the HDAC9 gene are prominent in large artery stroke and coronary artery disease and that upregulated HDAC9 expression is localized in endothelial cells of carotid atherosclerotic human tissue suggesting HDAC9 may play an important role in atherogenesis. Therefore, we hypothesized that vascular HDAC9 upregulation promotes endothelial dysfunction in MSEW mice via increased ET‐1. MSEW involves maternal separation 4 h/day (postnatal (PD) 2 to 5) and 8 h/day (PD6 to 16) and weaned at PD17. Normally reared litters weaned at PD21 were used as controls (CON). In adult male CON and MSEW mice, we determined aortic localization of HDAC9 and ET‐1. Immunohistolocalization showed aortic HDAC9 is upregulated specifically in the endothelial cells of MSEW mice (n=5/group). Confocal immunofluorescence imaging revealed aortic ET‐1 expression is also localized in the endothelium of both CON and MSEW mice. To examine the effects of endothelial HDAC9 on ET‐1 expression, we used mouse aortic endothelial cells (MAECs) transfected with control vector or HDAC9 plasmid incubated in the presence or absence of TSA. Cultured MAECs treated with TSA blunted ET‐1 expression (70% decrease from vehicle, p&lt;0.05, n=3/group). Furthermore, HDAC9 over‐expression in cultured MAECs significantly increased ET‐1 expression (relative to control vector group, 1.0±0.08 vs 1.73±0.44 arbitrary units, p&lt;0.05, n=3/group) and TSA reduced the HDAC9‐dependent ET‐1 expression (1.68 fold decrease from control vector vehicle group, p&lt;0.05, n=3/group). Our findings indicate endothelial dysfunction previously observed in our MSEW mouse model may be mediated by HDAC9‐dependent elevated ET‐1 production. In conclusion, this study highlights the importance of ELS in the development of CVD and the implications of an epigenetic pathway as a potential mechanistic link.Support or Funding InformationNIH P01 HLP0169999; NIH K01 DK105038This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Role of Endothelin in the Pathophysiology of Migraine-a Systematic Review.

Vasoactive peptides play a key role in the attack-initiating cascade of migraine. Recent studies have highlighted a potentially important role for endothelin-1, a potent vasoconstrictor peptide, in migraine pathophysiology. Here, we review the current data on endothelin's involvement in migraine. We identified 23 articles. Nine studies reported on endothelin-1 plasma concentrations in patients with migraine, eight studies investigated relevant genetic associations, five studies investigated endothelin-1 and spreading depression in animals, and one randomized controlled clinical trial tested the efficacy of an endothelin antagonist in the acute treatment of migraine in patients both with and without aura. Elevated endothelin-1 plasma levels have been reported in the early phase of migraine attacks. Genetic abnormalities related to the endothelin type A receptor have been reported in migraineurs. Endothelin-1 potently induces spreading depression in animals, which may explain the connection between endothelial irritation and migraine aura. Endothelin-1 could be a primary factor in the attack-triggering cascade of migraine attacks with and without aura. Additional studies in humans and animal models are needed to further elucidate the role of endothelin-1 in migraine.

Neprilysin inhibition and endothelin-1 elevation: Focus on the kidney

Increasing the degree of renin-angiotensin system (RAS) blockade by combining ≥2 RAS blockers marginally increases efficacy, but results in more side effects. Hence, interference with other systems is currently being investigated, like potentiation of natriuretic peptides with neprilysin inhibitors. However, the neprilysin inhibitor thiorphan was recently found to increase endothelin-1 when administered to TGR(mREN2)27 (Ren2) rats on top of RAS blockade. Here we investigated whether this effect is thiorphan-specific, by comparing the neprilysin inhibitors thiorphan and sacubitril, administered by osmotic minipumps at a low or high dose for 7 days, in Ren2 rats. Plasma and urinary levels of endothelin-1, atrial and brain natriuretic peptide (ANP, BNP) and their second messenger cyclic guanosine 3′5′ monophosphate (cGMP) were monitored. No significant differences were found in the plasma concentrations of endothelin-1, cGMP, ANP and BNP after treatment, although plasma ANP tended to be higher in the high-dose thiorphan treatment group and the low- and high-dose sacubitril treatment groups, compared with vehicle. Urinary endothelin-1 increased in the low-dose thiorphan and high-dose sacubitril groups, compared with baseline, although significance was reached for the former only. Urinary cGMP rose significantly in the high-dose sacubitril treatment group compared with baseline. Both urinary endothelin-1 and cGMP were significantly higher in the high-dose sacubitril group compared with the low-dose sacubitril group. In conclusion, endothelin-1 upregulation occurs with both thiorphan and sacubitril, and is particularly apparent in neprilysin-rich organs like the kidney. High renal neprilysin levels most likely also explain why sacubitril increased cGMP in urine only.

The transpulmonary ratio of endothelin 1 is elevated in patients with preserved left ventricular ejection fraction and combined pre- and post-capillary pulmonary hypertension.

Pulmonary hypertension complicating left heart disease (PH-LHD) is associated with increased morbidity and mortality, especially in patients who develop combined pre- and post-capillary PH (Cpc-PH). Mechanisms underlying PH-LHD are incompletely understood, particularly for individuals with preserved left ventricular ejection fraction (LVEF). We hypothesized that transpulmonary concentrations of biomarkers representing signaling pathways with known effects on the pulmonary circulation could provide insight into the molecular etiology of PH-LHD in patients with preserved LVEF. Blood samples were collected from the pulmonary artery (PA) and wedge positions of outpatients with normal LVEF referred for right heart catheterization. Hemodynamic tracings were reviewed to classify patients as “no PH” (n = 23) or “PH-LHD” (n = 22). A biomarker’s transpulmonary ratio (TPR) was calculated as the quotient of wedge and PA concentrations. The TPR of endothelin 1 (ET-1) was elevated in Cpc-PH (n = 10) compared to no PH or isolated post-capillary PH (Ipc-PH, n = 12); cAMP and cGMP TPRs were not different among groups. Higher ET-1 TPR in Cpc-PH was due to increased wedge ET-1 concentration. Pulmonary vascular resistance (PVR) strongly correlated with wedge ET-1 exclusively in Cpc-PH patients. In patients with normal LVEF and Cpc-PH, ET-1 TPR is higher, due to elevated wedge ET-1, compared to those without PH or with Ipc-PH. Strong correlation between PVR and wedge ET-1, observed only in the Cpc-PH group, may suggest increased pulmonary vascular responsiveness to ET-1 in these patients. These findings implicate elevated pulmonary ET-1 as a marker of, and a potential contributor to, development of Cpc-PH in this population.

Anti-inflammatory, Anti-oxidative and Athero-protective effects of Irbesartan in rabbits with Atherogenic diet

Abstract: The disorder of atherosclerosis is a dysfunction of endothelium due to inflammation of the blood vessel wall. In primary phases it characterized by activation and recruitment of macrophages. Irbesartan, an angiotensin receptor blocker, has ability to activate a peroxisome proliferator-activated receptor gamma. Numerous studies have been showed that management with angiotensin II blockers (ARBs) can alleviate formation of atherosclerotic plaque, however the underlining mechanism still obscure. Objectives: The present study is to evaluate the athero-protective actions of irbesartanvia reduction of inflammation and oxidative stress. Methods: This study enrolled twenty four male rabbits which were arbitrarily separated into 3 groups (every group contain 8 rabbits). All groups were fed for 12 weeks with normal chow (oxiod) diet (group I), normal chow (oxiod) diet with 0.05 % high cholesterol diet (Group II) and normal chow (oxiod) diet with 0.05 % high cholesterol diet together with 0.5 mg/kg irbesartanonce daily atmorning) (Group III). Samples of blood were analyzed at (time zero) and every 4 weeks of study to assess serum endothelin-1 (ED-1), intracellular adhesion molecule-1 (ICAM-1) and HDL-Cholesterol, triglycerides (TG), total cholesterol (TC). At the end the study (12 weeks) the aorta was collected to evaluate the aortic intimal thickness and the levels of aortic reduced glutathione (GSH) and aortic malondialdehyde (MDA). Results: Irbesartan treated group revealed in significant change of lipid parameters of when evaluate with group II (P > 0.05). However Irbesartan significantly decreased the elevated endothelin-1, Intracellular adhesion molecule-1, aortic intimal thickness and aortic MDA and restored aortic GSH level when compare with group II (P < 0.05). Conclusions: Irbesartan could participate in reduction of atherosclerosis progression in rabbit fed with rich cholesterol diet by interfering with inflammatory and oxidative pathways.

Abstract P270: First Trimester Elevation in Circulating Endothelin-1 and Arterial Stiffness are Predictive of Late Pregnancy Preeclampsia

Preeclampsia (PE) is characterized by late pregnancy hypertension and proteinuria. PE causes significant morbidity for the maternal-fetal unit. Circulating endothelin-1 (ET-1), a potent vasoconstrictor, is elevated at the time of diagnosis of human PE. In addition, women with PE demonstrate arterial stiffness as early as the end of the first trimester. However, it is unknown if arterial stiffness is associated with a first trimester elevation in ET-1 and post-delivery placental ET-1. We hypothesized that 1) first trimester plasma ET-1 is elevated and is associated with arterial stiffness in women who develop PE; 2) first trimester ET-1 is predictive of PE; and 3) placental ET-1 is increased in PE. To address these questions, we performed a nested case-control study in women at risk for PE. First trimester plasma ET-1 was measured via ELISA; aortic stiffness and carotid beta-stiffness (CβS) were measured by carotid-femoral pulse-wave velocity (CFPWV) and carotid tonometry/ultrasound, respectively. While the maternal age of controls (n=126; age 30 ± 0.45 years) and PE (n=15; age 31 ± 1.3 years) were similar, the PE group had a higher first trimester BMI (35 ± 3 vs. 29 ± 1 kg/m 2 , p = 0.01), systolic (125 ± 2 vs. 113 ± 1 mmHg, p&lt; 0.01) and diastolic blood pressure (68 ± 2 vs. 60 ± 1 mmHg, p&lt; 0.01) compared with controls. In addition, first trimester plasma ET-1 (2.7 ± 0.4 vs. 2.0 ± 0.2 pg/mL, p &lt; 0.01), CFPWV (7.2 ± 0.5 vs. 6.1 ± 0.2 m/s, p = 0.016), and CβS (8.4 ± 1.9 vs. 6.3 ± 0.3, p = 0.055) were higher in the PE group. Consistent with previous studies, third trimester plasma ET-1 was elevated in the PE group (2.9 ± 1.1 vs. 1.6 ± 0.1 pg/mL, p &lt; 0.01) which paralleled a 2.5 fold increase in placental decidual ET-1 mRNA (p &lt; 0.0001). ROC analyses showed that first trimester plasma ET-1 (AUC=0.71, p &lt; 0.001) and CFPWV (AUC=0.70, p=0.014) were predictive of PE. This study supports the novel concept that elevated ET-1 in preeclampsia begins early in the first trimester and is associated with premature arterial stiffness. Further, these novel data suggest that ET-1 may play an important role in the first trimester prediction and pathogenesis of preeclampsia.

Endothelin-1 is associated with dilatation of the left atrium and can be an independent predictor of atrial fibrillation after mitral valve surgery

This study analysed the association between endothelin-1 (ET-1) and left atrial dimension (LAD) and evaluated whether ET-1 can be a predictor of postoperative atrial fibrillation (POAF) after mitral valve surgery. This is a prospective study that enrolled 80 patients who underwent isolated mitral valve surgery. Plasma concentrations of ET-1 from peripheral venous blood were tested. POAF was detected using a telemetry strip or 12-lead electrocardiogram until the time of discharge. Patients undergoing mitral valve surgery with preoperative sinus rhythm (n = 80; average age 63.9 ± 7.9 years) were recruited to this study. POAF was documented in 31 (38.8%) patients. Preoperative plasma ET-1 levels were higher in patients with POAF compared to those without POAF (2.23 ± 0.67 vs 1.68 ± 0.59 pg/ml; P < 0.001). The plasma concentrations of ET-1 were positively correlated with LAD (Pearson's r = 0.421; P < 0.001). Multivariate logistic regression analysis revealed that LAD (odds ratio 1.170, 95% confidence interval 1.039-1.317; P = 0.009) and preoperative plasma ET-1 levels (upper versus lower 50th percentile: odds ratio 3.713, 95% confidence interval 1.085-12.701; P = 0.037) were predictors of POAF after mitral valve surgery. Plasma levels of ET-1 were positively correlated with LAD in patients with mitral valve disease. An elevated preoperative plasma ET-1 level can be used as a predictor of POAF after mitral valve surgery.

P 48 Low soluble Fms-like tyrosine kinase-1, endothelin-1 and endoglin levels in women with suspected or confirmed preeclampsia, using proton pump inhibitors

Preeclamptic patients display elevated placenta-derived soluble Fms-like tyrosine kinase-1 (sFlt-1), endoglin and endothelin-1 levels and decreased placental growth factor (PlGF) levels. Proton pump inhibitors (PPIs) have been reported to decrease trophoblast sFlt-1 secretion in vitro. PPIs are widely used during pregnancy, to combat reflux disease. To investigate whether PPIs affect sFlt-1, endoglin, endothelin-1 and PlGF in women with (suspected) preeclampsia. This is a secondary analysis of a prospective cohort study involving 430 singleton pregnant women with suspicion or with confirmed preeclampsia from 20 weeks gestation. As a comparator of the PPIs, the effects of other drugs commonly used in women with suspected or confirmed preeclampsia, i.e., antihypertensive drugs (α-methyldopa, nifedipine), corticosteroids, ferrous fumarate and macrogol, is simultaneously assessed. 40 (9%) out of the 430 patients were treated with PPIs (6 esomeprazol, 32 omeprazol and 2 pantoprazol) for 8–45 (mean 29) days before blood sampling. PPI use was associated with lower sFlt-1 levels, with no change in PlGF levels, both when compared to all non-PPI users, and to 80 gestational age-matched controls selected from the non-PPI users. No sFlt-1 or PlGF alterations were observed in women using ferrous fumarate or macrogol, while, as expected, women using antihypertensive medication displayed higher sFlt-1 levels and/or lower PlGF levels. The PPI use-associated decrease in sFlt-1 was independent of the application of antihypertensive drugs and also occurred when restricting our analysis to patients with hypertensive disease of pregnancy at study entry. PPI users displayed more cases with preexisting proteinuria, less gestational hypertension, and a lower number of neonatal sepsis cases. Furthermore, their plasma endoglin levels were lower along with their plasma endothelin-1 levels, while sFlt-1 levels correlated positively with endothelin-1 levels. PPI use associates with low sFlt-1, endothelin-1 and endoglin levels, warranting prospective trials to investigate the therapeutic potential of PPIs in preeclampsia.

Novel biomarkers for cardiovascular risk prediction.

Cardiovascular disease (CVD) is the leading cause of death and disability worldwide. The primary prevention of CVD is dependent upon the ability to identify high-risk individuals long before the development of overt events. This highlights the need for accurate risk stratification. An increasing number of novel biomarkers have been identified to predict cardiovascular events. Biomarkers play a critical role in the definition, prognostication, and decision-making regarding the management of cardiovascular events. This review focuses on a variety of promising biomarkers that provide diagnostic and prognostic information. The myocardial tissue-specific biomarker cardiac troponin, high-sensitivity assays for cardiac troponin, and heart-type fatty acid binding proteinall help diagnose myocardial infarction (MI) in the early hours following symptoms. Inflammatory markers such as growth differentiation factor-15, high-sensitivity C-reactive protein, fibrinogen, and uric acid predict MI and death. Pregnancy-associated plasma protein A, myeloperoxidase, and matrix metalloproteinases predict the risk of acute coronary syndrome. Lipoprotein-associated phospholipase A2 and secretory phospholipase A2 predict incident and recurrent cardiovascular events. Finally, elevated natriuretic peptides, ST2, endothelin-1, mid-regional-pro-adrenomedullin, copeptin, and galectin-3 have all been well validated to predict death and heart failure following a MI and provide risk stratification information for heart failure. Rapidly developing new areas, such as assessment of micro-RNA, are also explored. All the biomarkers reflect different aspects of the development of atherosclerosis.

Plasma ET-1 Concentrations are Elevated in Patients with Hypertension – Meta-Analysis of Clinical Studies

Background/Aims: A recent study revealed that global overexpression of ET-1 causes a slight reduction in systemic blood pressure. Moreover, heterozygous ET-1 knockout mice are hypertensive. The role of ET-1 in human hypertension was so far not addressed by a strict meta-analysis of published human clinical studies. Methods: We included studies published between January 1, 1990 and February 28, 2017. We included case control studies analyzing untreated essential hypertension or hypertensive patients where antihypertensive medication was discontinued for at least two weeks. Based on the principle of Cochrane systematic reviews, case control studies (CCSs) in PubMed (Medline) and Google Scholar designed to identify the role of endothelin-1 (ET-1) in the pathophysiological of hypertension were screened. Review Manager Version 5.0 (Rev-Man 5.0) was applied for statistical analysis. Mean difference and 95% confidence interval (CI) were shown in inverse variance (IV) fixed-effects model or IV random-effects models. Results: Eleven studies fulfilling our in- and exclusion criteria were eligible for this meta-analysis. These studies included 450 hypertensive patients and 328 controls. Our meta-analysis revealed that ET-1 plasma concentrations were higher in hypertensive patients as compared to the control patients [mean difference between groups 1.57 pg/mL, 95%CI [0.47∼2.68, P = 0.005]. These finding were driven by patients having systolic blood pressure higher than 160 mmHg and diastolic blood pressure higher than 100 mmHg. Conclusions: This meta-analysis showed that hypertensive patients do have elevated plasma ET-1 concentrations. This finding is driven by those patients with high systolic/diastolic blood pressure. Given that the ET-1 gene did not appear in any of the whole genome association studies searching for hypertension associated gene loci, it is very likely that the elevated plasma ET-1 concentrations in hypertensive patients are secondary to hypertension and may reflect endothelial cell damage.

Plasma ET-1 Concentrations Are Elevated in Pregnant Women with Hypertension -Meta-Analysis of Clinical Studies

Background/Aims: The ET system might be involved in the pathogenesis of hypertensive disorders during pregnancy. The objective is to analyse the impact of ET-1 in hypertensive pregnant women by a strict meta-analysis of published human clinical studies. Methods: Based on the principle of Cochrane systematic reviews, Cohort studies in PubMed (Medline), Google Scholar and China Biological Medicine Database (CBM-disc) designed to identify the role of endothelin-1 (ET-1) in the pathophysiology of gestational hypertension and preeclampsia were screened. Review Manager Version 5.0 (Rev-Man 5.0) was applied for statistical analysis. Mean difference and 95% confidence interval (CI) were shown in inverse variance (IV) fixed-effects model or IV random-effects model. Results: Sixteen published cohort studies including 1739 hypertensive cases and 409 controls were used in the meta-analysis. ET-1 plasma concentrations were higher in hypertensive pregnant women as compared to the controls (mean difference between groups: 19.02 [15.60～22.44], P < 0.00001,). These finding were driven by severity of hypertension and/or degree of proteinuria. Conclusion: Plasma ET-1 concentrations are elevated in hypertensive disorders during human pregnancy. In particular women with preeclampsia (hypertensive pregnant women with proteinuria) have substantially elevated plasma ET-1 concentration as compared to pregnant women with normal blood pressure.

Dual Endothelin-A/Endothelin-B Receptor Blockade and Cardiac Remodeling in Heart Failure With Preserved Ejection Fraction.

Despite the increasing prevalence of heart failure with preserved ejection fraction (HFpEF) in humans, there remains no evidence-based therapies for HFpEF. Endothelin-1 (ET-1) antagonists are a possibility because elevated ET-1 levels are associated with adverse cardiovascular effects, such as arterial and pulmonary vasoconstriction, impaired left ventricular (LV) relaxation, and stimulation of LV hypertrophy. LV hypertrophy is a common phenotype in HFpEF, particularly when associated with hypertension. In the present study, we found that ET-1 levels were significantly elevated in patients with chronic stable HFpEF. We then sought to investigate the effects of chronic macitentan, a dual ET-A/ET-B receptor antagonist, on cardiac structure and function in a murine model of HFpEF induced by chronic aldosterone infusion. Macitentan caused LV hypertrophy regression independent of blood pressure changes in HFpEF. Although macitentan did not modulate diastolic dysfunction in HFpEF, it significantly reduced wall thickness and relative wall thickness after 2 weeks of therapy. In vitro studies showed that macitentan decreased the aldosterone-induced cardiomyocyte hypertrophy. These changes were mediated by a reduction in the expression of cardiac myocyte enhancer factor 2a. Moreover, macitentan improved adverse cardiac remodeling, by reducing the stiffer cardiac collagen I and titin n2b expression in the left ventricle of mice with HFpEF. These findings indicate that dual ET-A/ET-B receptor inhibition improves HFpEF by abrogating adverse cardiac remodeling via antihypertrophic mechanisms and by reducing stiffness. Additional studies are needed to explore the role of dual ET-1 receptor antagonists in patients with HFpEF.

Obesity, type 2 diabetes, and impaired insulin-stimulated blood flow: role of skeletal muscle NO synthase and endothelin-1.

Although impairments in endothelial signaling are hypothesized to reduce insulin-stimulated blood flow in type 2 diabetes (T2D), human studies examining these links are limited. We provide the first measures of nitric oxide synthase and endothelin-1 expression from skeletal muscle tissue containing native microvessels in individuals with and without T2D before and during insulin stimulation. Higher basal skeletal muscle expression of endothelin-1 and reduced endothelial nitric oxide phosphorylation (peNOS)/eNOS may contribute to reduced insulin-stimulated blood flow in obese T2D patients.

Albuminuria Is Associated with Endothelial Dysfunction and Elevated Plasma Endothelin-1 in Sickle Cell Anemia.

BackgroundThe pathogenesis of albuminuria in SCD remains incompletely understood. We evaluated the association of albuminuria with measures of endothelial function, and explored associations of both albuminuria and measures of endothelial function with selected biological variables (vascular endothelial growth factor [VEGF], endothelin-1 [ET-1], soluble fms-like tyrosine kinase-1 [sFLT-1], soluble vascular cell adhesion molecule-1 [soluble VCAM-1] and plasma hemoglobin).MethodsSpot urine measurements for albumin-creatinine ratio (UACR) and 24-hour urine protein were obtained. Endothelial function was assessed using brachial artery ultrasound with measurements of flow-mediated dilation (FMD), nitroglycerin-mediated dilation (NTMD) and hyperemic velocity.ResultsTwenty three subjects with varying degrees of albuminuria were evaluated. UACR was significantly correlated with FMD (ρ = -0.45, p = 0.031). In univariate analysis, UACR was correlated with VEGF (ρ = -0.49; 95% CI: -0.75 –-0.1, p = 0.015), plasma hemoglobin (ρ = 0.50; 95% CI: 0.11–0.75, p = 0.013) and ET-1 (ρ = 0.40; 95% CI: -0.03–0.69, p = 0.06). Multivariable analysis showed significant associations of ET-1 (estimate: 455.1 [SE: 198.3], p = 0.02), VEGF (estimate: -1.1 [SE: 0.53], p = 0.04) and sFLT-1 (estimate: -1.14 [SE: 0.49], p = 0.02) with UACR. Only ET-1 (estimate: -8.03 [SE: 3.87], p = 0.04) was significantly associated with FMD in multivariable analyses. Finally, UACR was correlated with both 24-hour urine protein (ρ = 0.90, p < 0.0001) and urine aliquots for albumin-creatinine ratio obtained from the 24-hour urine collection (ρ = 0.97, p < 0.0001).ConclusionThis study provides more definitive evidence for the association of albuminuria with endothelial dysfunction in SCD. Elevated circulating levels of ET-1 may contribute to SCD-related glomerulopathy by mediating endothelial dysfunction.

The effect of hypoxia on intra-ocular, mean arterial, retinal venous and ocular perfusion pressures

High altitude hypoxia is linked to decreased blood oxygen saturation with a related increase of Endothelin-1 (ET-1) blood plasma levels. As a consequence of such elevated ET-1 levels, alterations of retinal venous and ocular perfusion pressures are suspected. To measure the effect of hypoxia on intra-ocular pressure, mean arterial pressure, retinal venous pressure and to calculate ocular perfusion pressure. An experimental, prospective cohort study with 33 healthy subjects was conducted in which the subjects were confronted with long-term (days) environmental hypoxia at high altitudes. Mean arterial pressure, arterial blood oxygen saturation, intra-ocular pressure, retinal venous and ocular perfusion pressure were measured at 300 m/1'000 ft (baseline), 4200 m/13'800 ft and 6000 m/19'700 ft above sea level. Arterial oxygen saturation (-13.06% ± 4.69, p = < 0.001; -23.46% ± 5.7,p = < 0.001), retinal venous pressure (+7.16 m Hg±8.2, p = < 0.001;+9.9 mm Hg±8.5, p = < 0.001) and ocular perfusion pressure (-8.49 mm Hg±10.6, p = < 0.001; -6.02 mm hg±11.2, p = 0.006) changed significantly from baseline at both high altitude of 4200 and 6000 m. Intra-ocular pressure did not change significantly at all altitudes (+1.16 mm Hg±4.5, p = 0.227; +0.84 mm Hg±4.8, p = 0.286) and mean arterial pressure changed significantly only at an altitude of 6000 m (+3,8 mm Hg±21.1, p = 0.005) from baseline. As hypoxia increases with higher altitude, arterial oxygen saturation and ocular perfusion pressure decreased, retinal venous pressure increased, intra-ocular pressure remains stable and mean arterial pressure was elevated only at 6000 m.

Association of Elevated Plasma Endothelin-1 Levels With Pulmonary Hypertension, Mortality, and Heart Failure in African American Individuals: The Jackson Heart Study.

Despite pathophysiological links between endothelin-1 and pulmonary vascular remodeling, to our knowledge, the association between plasma endothelin-1 levels and pulmonary hypertension has not been studied in the general population. Also, whether endothelin-1 can predict future heart failure and mortality, outcomes that are associated with pulmonary hypertension, in a population cohort is unclear. To determine whether elevated plasma endothelin-1 levels are associated with pulmonary hypertension, mortality, and heart failure. Data from the Jackson Heart Study, a longitudinal, prospective observational cohort study of heart disease in African American individuals from Jackson, Mississippi, were analyzed. The community population sample was limited to participants with detectable tricuspid regurgitation on echocardiography. The study participants included self-identified African American individuals with plasma endothelin-1 levels and tricuspid regurgitation on echocardiogram (n = 3223) at the time of first examination (2000-2004). The analysis of the data began on April 14, 2014, and was completed on February 23, 2016. Log-transformed plasma endothelin-1 level. Cross-sectional analysis: presence of pulmonary hypertension (defined as an elevated pulmonary artery systolic pressure >40 mm Hg on echocardiogram). Longitudinal outcomes were all-cause mortality (median follow-up, 7.75 years) and heart failure admissions (median follow-up, 5.32 years). Of the 3223 participants enrolled in the study, 1051 were men (32.6%). Mean (SD) endothelin-1 levels were 1.36 (0.64) pg/mL; 217 of 3223 cohort members (6.7%) had pulmonary hypertension. After adjusting for potential confounders, log-transformed endothelin-1 levels were associated with increased odds of pulmonary hypertension (adjusted odds ratio per log increment in endothelin-1, 1.66; 95% CI, 1.16-2.37). Log-transformed endothelin-1 levels were associated with mortality (adjusted hazard ratio per log increment in endothelin-1, 1.69; 95% CI, 1.27-2.25; median follow-up, 7.75 years) and heart failure (adjusted hazard ratio per log increment in endothelin-1, 1.57, 95% CI, 1.05-2.37; median follow-up, 5.32 years) in the study cohort. Phenotyping by pulmonary hypertension and endothelin-1 level showed mortality decreasing in order from subgroup with pulmonary hypertension and high endothelin-1 (high endothelin-1: ≥1.7 pg/mL; upper quartile); pulmonary hypertension and low endothelin-1 <1.7 pg/mL; lower 3 quartiles); no pulmonary hypertension and high endothelin-1; and no pulmonary hypertension and low endothelin-1 (log-rank χ2 = 77.16; P < .01 ). Elevated plasma endothelin-1 levels, especially associated with an elevated pulmonary artery systolic pressure on echocardiogram, may identify an at-risk population that could be evaluated for targeted prevention and management strategies in future studies.