endothelin 1
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2022 ◽  
Vol 23 (2) ◽  
pp. 927
Giovanni Civieri ◽  
Laura Iop ◽  
Francesco Tona

Angiotensin II receptor type 1 (AT1R) and endothelin-1 receptor type A (ETAR) are G-protein-coupled receptors (GPCRs) expressed on the surface of a great variety of cells: immune cells, vascular smooth cells, endothelial cells, and fibroblasts express ETAR and AT1R, which are activated by endothelin 1 (ET1) and angiotensin II (AngII), respectively. Certain autoantibodies are specific for these receptors and can regulate their function, thus being known as functional autoantibodies. The function of these antibodies is similar to that of natural ligands, and it involves not only vasoconstriction, but also the secretion of proinflammatory cytokines (such as interleukin-6 (IL6), IL8 and TNF-α), collagen production by fibroblasts, and reactive oxygen species (ROS) release by fibroblasts and neutrophils. The role of autoantibodies against AT1R and ETAR (AT1R-AAs and ETAR-AAs, respectively) is well described in the pathogenesis of many medical conditions (e.g., systemic sclerosis (SSc) and SSc-associated pulmonary hypertension, cystic fibrosis, and allograft dysfunction), but their implications in cardiovascular diseases are still unclear. This review summarizes the current evidence regarding the effects of AT1R-AAs and ETAR-AAs in cardiovascular pathologies, highlighting their roles in heart transplantation and mechanical circulatory support, preeclampsia, and acute coronary syndromes.

2022 ◽  
Vol 13 (1) ◽  
Liping Su ◽  
Xiaocen Kong ◽  
Szejie Loo ◽  
Yu Gao ◽  
Bingli Liu ◽  

Abstract Background Prior studies show that signature phenotypes of diabetic human induced pluripotent stem cells derived endothelial cells (dia-hiPSC-ECs) are disrupted glycine homeostasis, increased senescence, impaired mitochondrial function and angiogenic potential as compared with healthy hiPSC-ECs. In the current study, we aimed to assess the role of thymosin β-4 (Tb-4) on endothelial function using dia-hiPSC-ECs as disease model of endothelial dysfunction. Methods and results Using dia-hiPSC-ECs as models of endothelial dysfunction, we determined the effect of Tb-4 on cell proliferation, senescence, cyto-protection, protein expression of intercellular adhesion molecule-1 (ICAM-1), secretion of endothelin-1 and MMP-1, mitochondrial membrane potential, and cyto-protection in vitro and angiogenic potential for treatment of ischemic limb disease in a mouse model of type 2 diabetes mellitus (T2DM) in vivo. We found that 600 ng/mL Tb4 significantly up-regulated AKT activity and Bcl-XL protein expression, enhanced dia-hiPSC-EC viability and proliferation, limited senescence, reduced endothelin-1 and MMP-1 secretion, and improved reparative potency of dia-hiPSC-ECs for treatment of ischemic limb disease in mice with T2DM. However, Tb4 had no effect on improving mitochondrial membrane potential and glycine homeostasis and reducing intercellular adhesion molecule-1 protein expression in dia-hiPSC-ECs. Conclusions Tb-4 improves endothelial dysfunction through enhancing hiPSC-EC viability, reducing senescence and endothelin-1 production, and improves angiogenic potency in diabetes.

Pharmacia ◽  
2022 ◽  
Vol 69 (1) ◽  
pp. 31-35
Yuliia Ihorivna Mykula ◽  
Iryna Hryhorivna Kupnovytska ◽  
Oksana Ihorivna Danulyk

Chronic heart failure is one of the leading causes of death globally, affecting 1.5 to 2% of the total world population and 2.9 to 3.9% of the total Western European population. Chronic heart failure often progresses rapidly in coexistence with endocrine pathology, namely hypothyroidism, that results in a more rapid development and further progression of endothelial dysfunction and the development of a systemic inflammatory response. The aim of our research was to study the levels of endothelin-1, C-reactive protein, tumor necrosis factor α and their correlation with the levels of thyroid-stimulating hormone, thyroxine in patients with chronic heart failure and coexisting hypothyroidism. There were examined 38 patients with chronic heart failure and coexisting hypothyroidism and 42 patients with chronic heart failure without hypothyroidism. The serum levels of endothelin-1, C-reactive protein, tumor necrosis factor α were determined by the enzyme-linked immunosorbent assay, while the levels of thyroid-stimulating hormone and thyroxine were determined by the electrochemiluminescence immunoassay. In patients with chronic heart failure and coexisting hypothyroidism, the levels of endothelin-1, C-reactive protein, and tumor necrosis factor α were 2.9, 1.5 and 2.27 times higher than those in patients without hypothyroidism. In Group I, there was a moderate positive correlation between the serum levels of endothelin-1 and thyroid-stimulating hormone and a weak negative correlation between the levels of thyroxine and endothelin-1. In Group II, there was a weak correlation between the levels of endothelin-1 and thyroid-stimulating hormone and no correlation between the levels of thyroxine and endothelin-1. In Group I, there was a strong positive correlation between C-reactive protein and thyroid-stimulating hormone levels as well; in Group II, no similar correlation was found. In Group I, there was found a moderate negative correlation between tumor necrosis factor α and thyroxine levels. According to our results, there was a close correlation between the markers of endothelial dysfunction, immune inflammatory response, and single markers of hypothyroidism.

Arnaud D. Kaze ◽  
Xiang Gao ◽  
Solomon K. Musani ◽  
Aurelian Bidulescu ◽  
Alain G. Bertoni ◽  

2022 ◽  
George Abraham ◽  
Rhoda Kuc ◽  
Magnus Althage ◽  
Peter Greasley ◽  
Philip Ambery ◽  

Importance The coronavirus disease 2019 (Covid-19) pandemic continues to place a devastating strain on healthcare services worldwide and there remains an ongoing requirement for new treatments. A key mechanism recognised in progressive severe disease is virus-induced endothelial dysregulation. Endothelin-1 (ET-1), being the most highly expressed peptide in endothelial cells and potent vasoconstrictor of human blood vessels, represents a potential therapeutic target through the use of Endothelin receptor antagonists. Objective To investigate the association of plasma ET-1 with Covid-19 disease severity Design Retrospective longitudinal cohort study of Covid-19 patients divided into Group A (asymptomatic or symptoms not requiring hospitalisation), Group B (symptoms requiring hospitalisation) and Group C (symptoms requiring supplemental oxygen therapy or assisted ventilation) recruited between March and July 2020 (the first wave of the Covid-19 pandemic in the UK). Data were compared with a contemporaneous cross-section of non-infected volunteers (Controls). Setting Single Tertiary National Health Service Hospital. Participants Tissue banked plasma samples were obtained from 194 patients. Exposures Quantitation of ET-1 in plasma by specific enzyme linked immunosorbent assay. Main outcome and measures Pairwise comparison of ET-1 levels (median [IQR]) between patient categories, and subgroups defined by clinical outcomes. Results Baseline ET-1 plasma levels (pg/ml) were elevated in patients requiring hospitalisation compared with controls and patients with asymptomatic or mild infection (Group B: 1.59 [1.13-1.98], and Group C: 1.65 [1.02-2.32] versus controls: 0.68 [0.47-0.87], p=<0.001 and Group A: 0.72 [0.57-1.10], p=<0.001). ET-1 levels were also elevated in patients that died (2.09 [1.66-3.15]), developed acute kidney (1.70 [1.07-2.36]) or myocardial injury (1.50 [0.92-2.28]) compared with patients with an uncomplicated infection (1.00 [0.61-1.57], p=<0.01). Amongst surviving hospitalised patients, ET-1 concentrations decreased when measured at 28 days (Group B: 0.86 [0.60-1.61] and Group C: 1.17 [0.66-1.62] versus baseline, p=<0.05) and 90 days (Group B: 0.69 [0.59-1.38] and Group C: 1.01 [0.64-1.21] versus baseline, p=<0.05). Conclusions and relevance Hospitalised Covid-19 patients demonstrate elevated ET-1 levels during the acute phase of infection and this is associated with increasing clinical severity of the disease. The results support the hypothesis that endothelin receptor antagonists may be beneficial for certain Covid-19 patients.

Biomedicines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 86
Tzu-Hsien Chuang ◽  
Hsin-Yen Cho ◽  
Sheng-Nan Wu

Sparsentan is viewed as a dual antagonist of endothelin type A (ETA) receptor and angiotensin II (AngII) receptor and it could be beneficial in patients with focal segmental glomerulosclerosis. Moreover, it could improve glomerular filtration rate and augment protective tissue remodeling in mouse models of focal segmental glomerulosclerosis. The ionic mechanisms through which it interacts with the magnitude and/or gating kinetics of ionic currents in excitable cells were not thoroughly investigated. Herein, we aimed to examine the effects of varying sparsentan concentrations on ionic currents residing in pituitary GH3 somatolactotrophs. From whole-cell current recordings made in GH3 cells, sparsentan (0.3–100 μM) differentially inhibited the peak and late components of voltage-gated Na+ current (INa). The IC50 value of sparsentan required to exert a reduction in peak and late INa in GH3 cells was 15.04 and 1.21 μM, respectively; meanwhile, the KD value estimated from its shortening in the slow component of INa inactivation time constant was 2.09 μM. The sparsentan (10 μM) presence did not change the overall current–voltage relationship of INa; however, the steady-state inactivation curve of the current was shifted to more negative potential in its presence (10 μM), with no change in the gating charge of the curve. The window INa activated by a brief upsloping ramp was decreased during exposure to sparsentan (10 μM); moreover, recovery of peak INa became slowed in its presence. The Tefluthrin (Tef)-stimulated resurgent INa activated in response to abrupt depolarization followed by the descending ramp pulse was additionally attenuated by subsequent application of sparsentan. In continued presence of Tef (3 μM) or β-pompilidotoxin (3 μM), further application of sparsentan (3 μM) reversed their stimulation of INa. However, sparsentan-induced inhibition of INa failed to be overcome by subsequent application of either endothelin 1 (1 μM) or angiotensin II (1 μM); moreover, in continued presence of endothelin (1 μM) or angiotensin II (1 μM), further addition of sparsentan (3 μM) effectively decreased peak INa. Additionally, the application of sparsentan (3 μM) inhibited the peak and late components of erg-mediated K+ current in GH3 cells, although it mildly decreased the amplitude of delayed-rectifier K+ current. Altogether, this study provides a distinct yet unidentified finding that sparsentan may perturb the amplitude or gating of varying ionic currents in excitable cells.

Nephrology ◽  
2021 ◽  
Vol 4_2021 ◽  
pp. 8-15
M.Z. Gasanov Gasanov ◽  
M.G. Panchenko Panchenko ◽  
M.M. Batyushin Batyushin ◽  
N.A. Bronovitskaya Bronovitskaya ◽  
A.V. Razina Razina ◽  

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