Endothelin-1 Research Articles

Changes of maternal carotid artery elasticity in patients with pregnancy concurred with hypertension.

Echo-tracking (ET) technology can visually determine whether vascular endothelial function is impaired. However, it remains uncertain whether routine ET testing for pregnant women could effectively diagnose pregnancy concurrent with hypertension (PCH) based on changes in vascular elasticity. An ET ultrasound system was employed to assess the elasticity of the carotid artery. The plasma nitric oxide (NO) levels were determined using radioimmunoassay, and the levels of endothelin-1 (ET-1) were determined using an enzyme-linked immunosorbent assay. The prediction of PCH occurrence was assessed using receiver-operating characteristic curve analysis. The correlation between the two factors was evaluated using regression analysis. Pregnant women with PCH display significant differences in systolic blood pressure, diastolic blood pressure, and proteinuria compared to those with normal pregnancies. ET parameters, such as pulse wave velocity β (PWVβ), β-stiffness, pressure-strain elastic modulus (Eρ), and arterial compliance (AC), also reveal significant variances between women with PCH and those with normal pregnancies. These four factors are strongly associated with the disease progression in women with PCH and serve as reliable predictors for the occurrence of PCH. Additionally, the ET-1 level increases, while the NO level decreases in women with PCH, having the ability to predict the occurrence of PCH. Carotid endothelial elasticity decreases, and carotid endothelial function is impaired in pregnant women with PCH. The ET parameters and indexes of carotid endothelial function can reliably predict the occurrence of PCH.

A Game Changer for Resistant Hypertension: The Rise of Aprocitentan.

Hypertension is a major risk factor for cardiovascular disease (CVD), and a major contributor to global morbidity and mortality. In particular, resistant hypertension (rHTN), defined as blood pressure that remains elevated despite treatment with at least three antihypertensive agents including a diuretic, continues to be a major pharmacotherapeutic challenge. Traditional antihypertensive drugs often fail in patients with rHTN, underscoring the need for novel therapies. This is a brief mini-review of aprocitentan, a new drug that promises a glimmer of hope for rHTN patients. This drug is a dual endothelin (ET) receptor antagonist that blocks both ETA and ETB receptors. Given that these two receptors are critical players in vasotone regulation, antagonizing them, such as by aprocitentan, would be expected to significantly reduce blood pressure in patients with rHTN. Indeed, the PRECISION clinical trial demonstrated aprocitentan's superior effectiveness in reducing blood pressure in resistant patients, and the effects were sustained. Aprocitentan has been recently FDA-approved, marking a major milestone in hypertension management, offering hope for patients with difficult-to-treat hypertension.

Antihypertensive effect of sinapine extracted from rapeseed meal in 2K1C hypertensive rats

To extract sinapine from rapeseed meal and investigate its antihypertensive function and mechanism. Blood pressure was measured before and after sinapine administration to evaluate sinapine’s immediate antihypertensive function. Twokidney, oneclip (2K1C) hypertensive rats were given sinapine for four weeks, with weekly blood pressure monitoring. The renin angiotensin aldosterone system (RAAS), including the levels of renin, angiotensin I (Ang I), angiotensin II (Ang II), aldosterone (ALD), angiotensin-converting enzyme (ACE) and other molecules related to blood pressure, such as NO, prostacyclin (PGI2), endothelin-1 (ET1), and thromboxane A2 (TXA2), were measured in rat blood. The impact of sinapine on vascular endothelial cell (A10) calcium and potassium channels was assessed using the patch-clamp technique. One-time or long-term administration of sinapine significantly reduced the rats’ systolic blood pressure (SBP), diastolic pressure (DBP), and mean blood pressure (MBP). Sinapine also decreased the levels of Ang II and ALD. Furthermore, sinapine effectively inhibited ACE activation, increased NO levels, and blocked L-type calcium channels. Sinapine has an antihypertensive function and achieves this process through multiple targets.

Sodium valproate reverses aortic hypercontractility in acute myocardial infarction in rabbits.

Sympathetic nervous system (SNS), endothelin 1 (ET-1) and angiotensin II (Ang II) are involved in the pathophysiology of acute myocardial infarction (AMI). Valproic acid (VPA) is under study for the treatment against AMI due to its beneficial cardiac effects. However, the vascular effects of VPA on the activation of the SNS, ET-1 and Ang II after AMI are not fully studied. In our study, we used aorta from New Zealand White rabbits without AMI, with AMI and AMI treated with VPA (500mg/kg/day). AMI was induced by occluding the left circumflex coronary artery for 1h, followed by reperfusion. After 5 weeks, we studied the ex vivo vascular reactivity in organ bath and measured protein expression by Western blot. Our findings indicated that AMI increased vasoconstriction to exogenous and endogenous NE and ET-1, which was reversed by VPA eliciting upregulation of α2-adrenergic and ETB receptors and downregulating ETA receptors. Although no changes in the vascular response to Ang II were observed in AMI or VPA-treated rabbits, an increase in Ang II type 2 receptor expression was found in VPA-treated rabbits. We conclude that VPA could be considered a vascular protector by modulating SNS, ET-1 and Ang II in the aorta, which together with its cardioprotective effect would make it a promising candidate for the treatment of AMI.

Repurposing bosentan as an anticancer agent: EGFR/ERK/c-Jun modulation inhibits NSCLC tumor growth.

Drug repurposing of well-established drugs to be targeted against lung cancer has been a promising strategy. Bosentan is an endothelin 1 (ET-1) blocker widely used in pulmonary hypertension. The current experiment intends to inspect the anticancer and antiangiogenic mechanism of bosentan targeting epidermal growth factor receptor (EGFR) /extra-cellular Signal Regulated Kinase (ERK) /c-Jun/vascular endothelial growth factor (VEGF) carcinogenic pathway. BALB/c mice were randomized into four groups, the first received the vehicle, the second received 100 mg/kg oral bosentan alone, the third has non-small cell lung cancer (NSCLC) induced by two doses of 1.5g/kg urethane i.p. and finally the fourth has NSCLC received bosentan. To determine the anti-proliferative impact of bosentan, cytokeratin 19 fragments (CYFRA 21-1) level was assessed, and Ki-67 positive cells were counted by immunohistochemical (IHC). Molecular expression of EGFR via IHC, relative expression of p-ERK1/2 and p-c-Jun via western blotting and caspase 3, Bcl-2 Associated X-protein (BAX)/B-cell lymphoma 2 (Bcl-2) ratio and VEGF via ELISA were quantified. Bosentan showed pronounced improvement in lung index and histopathological examinations. Bosentan exerted a noticeable arrest of lung cancer growth indicated by the attenuation of CYFRA 21-1 and Ki-67 positive cell counts besides the boost of BAX/Bcl-2 ratio and caspase 3. Bosentan induced a remarkable decline of EGFR, T-ERK1/2/p-ERK1/2, T-c-Jun/p-c-Jun, and VEGF. Bosentan induced cytotoxic and anti-angiogenic impact through regulation of EGFR/ERK/c-Jun/VEGF axis suggesting its potential therapeutic impact against lung cancer.

Endothelial dysfunction in middle-aged and older men with low testosterone is associated with elevated circulating endothelin-1.

Low testosterone in middle-aged/older men contributes to accelerated vascular aging, including endothelial dysfunction. However, the mechanisms by which low testosterone affects endothelial dysfunction are not well understood. We sought to determine whether higher endothelin-1 (ET-1) levels are associated with reduced brachial artery flow-mediated dilation (FMD) in middle-aged/older men with low testosterone. METHODS: Plasma ET-1 was quantified in 60 men categorized as young (N=20, age=30±4 y, testosterone=510±63 ng/dL), middle-aged/older with normal testosterone (N=20, age=59±6 y, testosterone=512±115 ng/dL), or middle-aged/older with low testosterone (N=20, age=60±8 y, testosterone=265±47 ng/dL). Endothelial function was determined via FMD. Venous and arterial endothelial cells were harvested in a subset of participants and stained for ET-1 expression. RESULTS: Middle-aged/older men with normal testosterone exhibited lower brachial artery FMD (5.7±2.2%) compared to young men (7.3±1.3%, p=0.020), which was exaggerated in middle-aged/older men with low testosterone (4.0±1.8%, p=0.010 vs, middle-aged/older men with normal testosterone). Plasma ET-1 was not different between young (5.6±0.9 ng/dL) and middle-aged/older men with normal testosterone (6.0±1.4 ng/dL p=0.681) but was higher in middle-aged/older men with low testosterone (7.7±2.8 ng/dL) compared to both groups (p<0.001 vs. young men; p=0.013 vs. middle-aged/older men with normal testosterone). There was no difference in venous (p=0.616) or arterial (p=0.222) endothelial cell ET-1 expression between groups. There was a significant inverse association between plasma ET-1 and FMD (r=-0.371, p=0.004). CONCLUSIONS: These data suggest that the accelerated age-associated reduction in endothelial dysfunction in middle-aged/older men with low testosterone is related to higher circulating ET-1.

Enhanced vascular contraction induced by exposure to angiotensin II mediated by endothelin-1 biosynthesis following PKCβ activation.

Protein kinase C (PKC) reportedly plays a role in the pathogenesis of many vascular dysfunction-related conditions. In this study, we investigated whether PKCβ is associated with vascular contractile changes induced by angiotensin II (Ang II) exposure. Long-term (24 h) treatment of rat aortae and mesenteric arteries in Ang II-containing culture medium enhanced 5-hydroxytrypatamine (5-HT)-induced vascular contraction in a dose-dependent manner, in association with enhanced phosphorylation of PKCβ S660. Increased contraction induced by Ang II treatment was also observed in endothelium-denuded aorta. Enhanced contraction induced by Ang II was markedly diminished by knockout of the PKCβ gene or treatment with LY333531 and CGP53353 (PKCβ inhibitors). Cycloheximide (protein synthesis inhibitor) blocked the Ang II-induced enhanced contraction. Gene expression profiling and real-time PCR analyses showed marked upregulation of endothelin-1 (ET-1) expression in Ang II-treated aorta, but was not observed in PKCβ-knockout aorta. Ang II increased the secretion of ET-1 peptide in endothelium-intact and -denuded aortae. Ang II-induced enhancement of vascular contraction was diminished by BQ-123 (ETAR blocker). In vivo treatment with Ang II (250 ng/kg/min) for 7 days increased phosphorylation of PKCβ S660 in rat vascular tissue and increased the in vitro contractile responses to 5-HT and in vivo systolic blood pressure, but these changes were largely absent in PKCβ-knockout experiments. These data suggest that long-term exposure to Ang II increases vascular smooth muscle contraction and blood pressure elevation, mediated by activation of PKCβ and subsequent biosynthesis of ET-1 in vascular smooth muscle cells.

Inhibition of p75NTR/p53 axis by ambrisentan suppresses apoptosis and oxidative stress-mediated renal damage in a cisplatin AKI model.

Cisplatin (CP) is a potent antineoplastic agent that triggers nephrotoxicity as a major adverse effect which can cause treatment interruptions and limitations to its clinical use. Nephrotoxicity associated with CP involves inflammation, oxidative stress and apoptosis in kidney tubules. The objective of this work was to assess the effect of the blockade of endothelin-1 (ET-1) receptor with ambrisentan (Amb) on altered renal function induced by CP. Swiss albino mice were assigned into control, CP, CP/Amb-5 and CP/Amb-10 groups. Ambrisentan improved kidney function (serum creatinine and BUN) and histopathological changes in comparison to CP-treated group. Ambrisentan significantly reduced protein expression of p75NTR and JNK influencing renal apoptosis as evidenced by reducing p53, caspase-3 and Bax level and elevating Bcl-2 level (p<0.05 vs CP group). Moreover, vasodilatory effect of ambrisentan was indicated by significant increase in level of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) (p<0.05 vs CP group). Ambrisentan also significantly restored oxidative balance in renal tissues as evidenced by reduced malondialdehyde and increased total antioxidant capacity and superoxide dismutase activity, in addition to decreasing nitric oxide levels (p<0.05 vs CP group). This protective effect of ambrisentan might be mediated through the downregulation of death receptor, P75NTR that in turn restores renal blood flow and oxidative balance and regulates p53, VEGF/eNOS, NF-κB, and bcl-2/Bax/caspase-3 signaling.

Small ubiquitin-like modifiers inhibitors lower blood pressure via ERK5/KLF2-dependent upregulation of the eNOS/NO pathway

Abstract Background Small ubiquitin-like modifiers (SUMO)ylation is a dynamic and reversible post-translational modification playing pivotal roles in the regulation of cancer, diabetes, heart failure, and neurological diseases. However, whether SUMO inhibitors also have anti-hypertension effect remains yet to be explored. Methods Blood pressure was monitored in spontaneously hypertensive rats (SHR) after Tannic acid (TA) administration for 4 weeks. The contents of nitric oxide (NO) and endothelin-1 (ET-1) in the serum of SHR were measured. Isolated endothelium-intact mesenteric artery rings were used to study relaxation effect of SUMO inhibitors. ERK5 SUMOylation was determined using coimmunoprecipitation (co-IP) and immunofluorescence (IF). NO levels were analyzed by IF. The expression levels of KLF2 and p-eNOS were semiquantified by Western blot analysis. The transcriptional activity of eNOS promotor was assayed using ChIP-PCR. Results Three SUMO inhibitors all reduced the phenylephrine (PE)-induced contraction of mesenteric artery rings in a concentration-dependent manner. Co-IP revealed that ponatinib promoted ERK5 SUMOylation, which was nulled following pretreatment with the SUMO inhibitors. IF displayed that TA increased ERK5 accumulation and its co-localization with SUMO-1 in the nucleus. ChIP-PCR unveiled TA-induced enhancement of KLF2-dependent eNOS promoter activity and upregulation of eNOS/NO expression in HUVECs. In vivo, TA significantly lowered the blood pressure and improved the vascular reactivity by activating the KLF2/eNOS/NO pathway. Additionally, the level of NO was elevated along with decreased ET-1 levels in the serum of SHR. Conclusions SUMO inhibitors inhibit ERK5 SUMOylation to promote KLF2-eNOS/NO signaling, indicating their therapeutic potential for the treatment of hypertension.

Differences in Plasma Endothelin-1 Levels Before and After MgSO4 Administration in Pregnant Women with Preeclampsia

Introduction: Preeclampsia (PE) is a major cause of maternal morbidity and mortality, particularly in low-resource settings. Although Magnesium Sulfate (MgSO4) is the standard treatment for preventing eclampsia, its precise effects on vascular function, especially regarding Endothelin-1 (ET-1) levels, remain unclear. ET-1, a potent vasoconstrictor, is elevated in hypertensive disorders of pregnancy, contributing to endothelial dysfunction in PE. This study aims to investigate the impact of MgSO4 therapy on plasma ET-1 levels in pregnant women diagnosed with severe PE. Method: This observational follow-up study was conducted at RSUP Prof. Dr. I. G. N. G. Ngoerah, Denpasar, starting in October 2022. Participants included pregnant women with severe PE, aged 20–40 weeks of gestation, receiving MgSO4 therapy. Patients with chronic conditions such as diabetes or pre-existing hypertension were excluded. Blood samples were collected before and after MgSO4 administration, and plasma ET-1 levels were measured using enzyme-linked immunosorbent assay (ELISA). Statistical analysis was conducted using the Wilcoxon test, with a significance level set at p &lt; 0.05. Results: A total of 31 participants, with a mean age of 32.09 ± 6.48 years, were included. Most patients were nulliparous (32.3%) and had a single marriage history (71.0%). Baseline characteristics showed high systolic and diastolic blood pressures (mean 165 and 110 mmHg, respectively), elevated MAP (131 mmHg), and significant proteinuria (+3 in 38.7% of cases). Laboratory results indicated abnormal levels of AST, ALT, LDH, and creatinine, with an average platelet count of 241.35 ± 69.77 x 103/L. Following MgSO4 therapy, ET-1 levels significantly decreased from a median of 12.45 ng/mL to 5.55 ng/mL (p = 0.004), suggesting an improvement in endothelial function. Conclusion: The study findings suggest that MgSO4 not only prevents seizures but also plays a role in reducing vasoconstriction in PE patients through the modulation of ET-1 levels. This supports the potential use of ET-1 as a marker to evaluate the therapeutic efficacy of MgSO4 in PE management, highlighting MgSO4’s broader vascular benefits in treating PE.

Molecular Mechanisms of Vascular Tone in Exercising Pediatric Populations: A Comprehensive Overview on Endothelial, Antioxidative, Metabolic and Lipoprotein Signaling Molecules

Vasoactive molecules are central regulators of vascular tone, angiogenesis and inflammation. Key molecular agents include nitric oxide (NO), endothelin-1 (ET-1), prostacyclin, free triiodothyronine (fT3), leptin, low-density lipoprotein (LDL), high-density lipoprotein (HDL), superoxide dismutase (SOD), and glutathione peroxidase (GPX). Dysregulation of these compounds can lead to endothelial dysfunction, an early predictor of atherosclerosis and cardiovascular diseases (CVD). Maintaining endothelial health is thus essential for vascular homeostasis and cardiovascular risk prevention. Regular exercise serves as a vital protective measure against CVD and the risk of cardiovascular conditions. However, young athletes often significantly exceed recommended levels of training load, engaging in highly intensive training that leads to substantial physiological adaptations. Despite this, research on the impact of exercise on vasoactive substances in children and adolescents, particularly young athletes, is limited and inconsistent. Most studies focus on those with pre-existing conditions, like obesity or diabetes mellitus. Existing findings suggest exercise may favorably affect vascular biomarkers in youth, but methodological variations hinder consistent conclusions. This literature review examines 68 studies on the effects of exercise on vascular molecules in children and adolescents, young athletes, and children and adolescents with pre-existing conditions, offering deeper insights into how exercise may influence vascular health at the molecular level.

Increased aqueous humor levels of endothelin-1 in patients with open angle glaucoma

BackgroundEndothelin is a potent vasoconstrictor and contributes to the regulation of vascular perfusion. Aberrant endothelin-1 (ET-1) levels in aqueous humor have been reported across a variety of vascular diseases of the eye, including glaucoma. These findings suggest that dysregulation of ET-1 production may contribute to glaucoma pathophysiology. In this study, aqueous humor from patients undergoing ocular surgery was assayed for ET-1 abundance and related to the presence of glaucoma.PatientsOpen angle glaucoma patients (n=62 total) from the ophthalmology clinics of the University of Iowa Hospitals and Clinics were enrolled in this study and organized into three distinct cohorts based on their diagnostic criteria, including those with primary open angle glaucoma (POAG, n=25 patients), normal tension glaucoma (NTG, n=17 patients), exfoliation glaucoma (XFG, n=8 patients), and normal controls (n=12 patients).MethodsAqueous humor was collected intraoperatively from patients undergoing surgeries for glaucoma (including minimally invasive glaucoma surgeries, trabeculectomy, or glaucoma drainage device implantation) for samples in the glaucoma cohorts and cataract extraction for those in the control cohort. Aqueous humor was assayed by ELISA to measure and compare ET-1 abundance between the glaucoma cohorts and control cohort. ET-1 levels were also analyzed with linear regression to control for the covariates of age and sex.ResultsET-1 was significantly elevated in the aqueous humor of patients in the POAG (mean ± SD: 7.8 ± 5.1 pg/mL; p = 0.002) and NTG cohorts (6.1 ± 3.0 pg/mL; p = 0.030) compared to the control (4.0 ± 1.9 pg/mL). No significant difference in aqueous ET-1 was detected in the XFG cohort (6.2 ± 4.5 pg/mL; p = 0.230) compared to the control. Significantly higher ET-1 levels were detected in a merged grouping of all glaucoma cohorts (POAG, NTG, XFG) relative to controls (p = 0.021). Analysis of covariance indicated neither age nor sex was associated with ET-1 level (p = 0.60 and p = 0.27), respectively. Controlling for age and sex had minimal influence on the comparison of ET-1 levels in the POAG versus control cohort (p = 0.018) and nominal influence on the comparisons between the NTG (p = 0.089) or XFG cohort (p = 0.15) relative to the control.ConclusionsElevated ET-1 in aqueous humor was associated with POAG and NTG compared to controls amongst cohorts of patients at the University of Iowa. These data suggest that dysregulation of vascular perfusion may have a role in the pathophysiology of POAG. The analyses of NTG and XFG samples were limited by the relatively small sample sizes.

Diagnostic and prognostic biomarkers at idiopathic pulmonary arterial hypertension

Introduction. Idiopathic pulmonary arterial hypertension (IPAH) is a subtype of pulmonary arterial hypertension (PAH). IPAH is characterized by a progressive increase in pulmonary vascular resistance (PVR), which can lead to right ventricular heart failure and even mortality. The aim was to study the levels of C-reactive protein (CRP), endothelin-1 (ET-1) and interleukin-6 (IL-6) in patients with IPAH, as well as to assess their relationship with clinical and hemodynamic parameters.Materials and methods. Expression of CRP, ET-1 and IL-6 in blood serum samples of patients with IPAH (n=53) and control group (n=52) of the appropriate age/gender was determined using enzyme immunoassay (ELISA). Demographic, clinical characteristics and hemodynamic parameters were studied in patients with IPAH according to catheterization of the right heart (CRH).Result and discussion. The average age range of patients with IPAH was 35.0-51.0 years, there were 46 (86.8%) women in this group. The average age of the participants in the control group was 31.0-42.0 years, there were 46 (88.5%) women. The levels of ET-1 (p &lt; .016) and IL-6 (p &lt; .001) were higher in patients with IPAH compared to patients in the control group, whereas the level of CRP (p = .270) was no different. Meanwhile, the level of ET-1 positively correlated with the average pressure in the right atrium (r = .728, p &lt; .001) and pulmonary vascular resistance (r = .360, p = .008), while IL-6 positively correlated with the functional class of heart failure according to the classification of the New York Heart Association (NYHA FC).Conclusion. Levels of IL-6 and ET-1 can be included in the diagnostic algorithm for assessing the severity and prognosis of the disease.

Plasma Endothelin-1 Levels: Non-Predictors of Alzheimer's Disease Reveal Age Correlation in African American Women.

Background/Objectives: Alzheimer's disease (AD) and related dementias (ADRD) disproportionately impact racial and ethnic minorities. Contributing biological factors that explain this disparity have been elusive. Moreover, non-invasive biomarkers for early detection of AD are needed. Endothelin-1 (ET-1), a vasoconstrictive factor linked to cerebral vascular disease pathology and neuronal injury, could provide insights to better understand racial disparities in AD. As a potent vasoconstrictive peptide that regulates contractions in smooth muscle, endothelial cells, and pericytes, ET-1 may result in cerebral vascular constriction, leading to cerebral hypoperfusion; over time, this may result in neuronal injury, contributing to the pathology of AD. The role of the ET-1 system as a driver of ethnic disparities in AD requires further investigation. In the United States (U.S.), ET-1 dysregulation in Hispanic/Latinx (H/L) ethnic populations has largely been unexplored. Genetics linking ET-1 dysregulation and racial disparities in AD also require further investigation. In this study, we examined the role of the ET-1 protein in human plasma as a potential biomarker with predictive value for correlating with the development of AD by age, race, and sex. Methods: We examined ET-1 protein levels using quantitative mass spectrometry in AA and NHW patients with AD, along with controls. Results: A partial correlation between age at draw and ET-1, stratified by race and sex, while controlling for AD status, was significant for female AAs (r = 0.385, p = 0.016). When the data were not stratified but controlled for AD status, the partial correlation between age at draw and ET-1 was not significant (r = 0.108, p = 0.259). Conclusions: Based on the small number of plasma specimens and no plasma specimens from H/L individuals with AD, we conclude that ET-1 was clearly not a significant factor in predicting AD in this study and will require a larger scale study for validation.

Reviewing the path to balance: mechanisms and management of hypertension associated with targeting vascular endothelium in cancer therapy.

Contemporary anticancer drugs are often accompanied by varying degrees of cardiovascular toxicity, with hypertension emerging as one of the most prevalent side effects, particularly linked to inhibitors of vascular endothelial growth factor receptor (VEGFR) and tyrosine kinase inhibitors (TKIs). Hypertension induced by cancer therapies contributes to increased cardiovascular mortality in cancer patients and survivors. Given the shared common risk factors and overlapping pathophysiological mechanisms, hypertension is also a prevalent comorbidity in this patient population. The mechanisms underlying hypertension induced by therapies targeting the vascular endothelial growth factor (VEGF) signaling pathway primarily involve reduced nitric oxide (NO) synthesis, increased endothelin-1 (ET-1) production, oxidative stress, microvascular rarefaction and dysfunction, decreased natriuresis, activation of the renin-angiotensin system (RAS), and partial endothelial cell death. Research into hypertension associated with therapies targeting the VEGF signaling pathway (VSP) could facilitate the optimization of cancer treatments, improve the evaluation and management of hypertension during targeted therapy, and help to reduce cardiovascular event rates and overall patient mortality. This review aims to provide a comprehensive summary of the current advancements in this area.

ALIGNing the treatment of IgA nephropathy: Reducing proteinuria with endothelin A receptor inhibition.

The ALIGN trial1 demonstrates that atrasentan, an endothelin A (ETA) receptor antagonist, reduces proteinuria in patients with IgA nephropathy (IgAN), a key goal to slow progressive renal disease. These results are consistent with those from sparsentan,2,3 a combined ETA and angiotensin inhibitor, in IgAN, suggesting two-year data will show atrasentan improves renal outcomes.

Features of infl ammatory biomarkers in patients with occupational COPD and cardiovascular comorbidity

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, with over 30% of these patients dying from cardiovascular diseases. Objective: to study the pathophysiological links between echocardiography, spirometry indicators, and inflammatory biomarkers in patients with various clinical phenotypes of occupational COPD with cardiovascular comorbidity. Material and methods. The study included 111 patients with occupational COPD and cardiovascular comorbidity. Based on spirometry results, patients were divided into 4 groups (clinical phenotypes). Clinical examinations, echocardiography, and serum concentrations of troponin I, endothelin-1 (E-1), endothelial synthase (ES), hyaluronic acid (HA), and myoglobin were performed. Results. The concentrations of troponin I, myoglobin, and E-1 were normal in all groups. HA concentration was highest among phenotype “E” patients (p = 0.0008). ES concentration in phenotype “E” was more than 2.5 times higher compared to other groups (p = 0.0022). Myoglobin concentration positively correlated with left ventricular myocardium thickness, ES, eosinophil levels, and coronary heart disease (p &lt; 0.05), while ES concentration correlated positively with hypertension. HA concentration negatively correlated with spirometry and echocardiography indicators and positively correlated with eosinophil levels and exacerbations (p &lt; 0.05). Conclusion. Further research is needed to identify biomarkers reflecting the risk of exacerbations in cardiovascular comorbidities in patients with occupational COPD

Predictive Value of Selected Plasma Biomarkers in the Assessment of the Occurrence and Severity of Coronary Artery Disease.

Despite significant advances in imaging modalities for diagnosing coronary artery disease (CAD), there remains a need for novel diagnostic approaches with high predictive values and fewer limitations. Circulating biomarkers, including cytokines such as interleukin-6 (IL-6) and interleukin-8 (IL-8), cell adhesion molecules such as soluble vascular cell adhesion molecule-1 (sVCAM-1), peptides secreted by endothelial cells such as endothelin-1 (ET-1), and enzymes involved in extracellular matrix remodeling such as a disintegrin and metalloproteinase with thrombospondin motifs-1 (ADAMTS-1) offer a promising alternative. This study aimed to evaluate the correlation between the plasma levels of selected biomarkers and the presence and severity of CAD. We enrolled 40 patients admitted for elective coronary angiography. CAD was defined as having at least one coronary artery stenosis ≥ 50%. The severity of CAD was assessed using the Gensini Score (GS). IL-8 levels were significantly higher in the CAD group, with a mean of 9.78 (SD 0.46) compared to 8.37 (SD 0.40) in the non-CAD group (p = 0.0228). No significant differences were observed for the other biomarkers between the groups. A positive Spearman correlation was found between IL-8 levels and the GS (ρ = 0.39, p = 0.017). These findings suggest that IL-8 may have potential as an additional tool for diagnosing or excluding atherosclerosis. Further studies with larger sample sizes are needed to validate its clinical utility.

EDNRB negatively regulates glycolysis to exhibit anti-tumor functions in prostate cancer by cGMP/PKG pathway.

Prostate cancer (PCa) is the most prevalent cancer in men and the leading cause of cancer-related mortality. Recent studies have highlighted the pivotal role of glycolysis in tumor progression. This study aimed to investigate the involvement of the EDNRB gene and its ligand endothelin 3 (EDN3) in glycolysis in PCa and to elucidate its underlying molecular mechanism. Quantitative reverse transcription PCR (RT-qPCR) and methylation-specific PCR (MSP) were used to probe EDNRB expression and methylation in PCa tissues. Cell proliferation and glycolysis in PCa cells were evaluated using Cell Counting Kit-8 (CCK-8), EDU staining, Seahorse assay, and biochemical kits to analyze the effects of EDN3/EDNRB. The underlying molecular mechanism was further explored through Western blotting. The in vivo effect of EDNRB on tumor growth was examined using a xenograft tumor model. Our findings revealed that EDNRB was hypermethylated and downregulated in PCa tissues and cell lines. Overexpression of EDNRB or EDN3 led to reduced cell proliferation and downregulation of glycolytic markers. EDNRB also decreased the extracellular acidification rate (ECAR) baseline and increased the oxygen consumption rate (OCR) baseline, indicating a shift away from glycolysis. Additionally, the anticancer effects of EDNRB or EDN3 was reversed upon inhibition of the cGMP/PKG pathway. In vivo, enhanced EDNRB expression significantly suppressed tumor growth. Therefore, EDNRB or EDN3 possess anticancer potential in PCa, primarily through the regulation of glycolysis via the cGMP/PKG pathway.

Association of endothelial nitric oxide synthase (NOS3) rs2070744 variant with advanced retinopathy of prematurity: a case–control study and meta-analysis

Despite advances in neonatal and ophthalmological care, retinopathy of prematurity (ROP) continues to be a leading cause of childhood blindness worldwide. Investigating gene variants associated with vascular responses in ROP may provide valuable insights into its pathogenesis and identify risk or protective factors. Nitric oxide (NO) and endothelin-1 (ET-1) play roles in vascular regulation, influencing processes relevant to ROP development. Functional variants of genes encoding endothelial NO sythetase (NOS3 rs1799983, rs2070744), endothelin-1 (EDN1 rs5370), and endothelin receptor A (EDNRA rs5335) may influence ROP development or progression. The results of our study support the role of the rs2070744 variant in ROP. We identified the protective effect of the rs2070744C allele against the development of ROP requiring treatment, also after adjusting for covariates. Meta-analysis including 298 patients and 397 controls confirmed this protective role. The rs2070744CC homozygous genotype exhibited an odds ratio (OR) of 0.42 (adjusted P = 0.036). Additional meta-analysis results for NOS3 rs1799983 are presented, suggesting potential risk in a recessive model. No associations were found between EDN1, EDNRA variants, and ROP. Exploring genetic predispositions in ROP, including vascular regulation genes, can lead to personalized prevention and treatment approaches. Our results need to be replicated in a larger sample of premature infants.