Rapid communicationEndothelin receptor A expression in human inflammatory cells
Introduction
The family of endothelins (ETs), a group of polyfunctional cytokines, is composed of three isoforms (ET-1, ET-2, ET-3) of which the more studied is ET-1, the most potent vasoconstrictor that has also a growth-promoting function [1].
ET-1 is formed by the catalytic action of ECE-1 on precursor big ET-1, and its cellular actions are mediated via ET receptors (ETA, ETB) that are G protein-coupled seven transmembrane-spanning receptors and it is well known that these kinds of receptors are also the major targets for many of the currently available drugs, including cardiovascular and immunomodulatory agents [2]. ETA and ETB receptors are widely expressed in all human vessels, consistent with the main role of ET-1 in maintaining the physiological vascular tone [1].
Furthermore, the peptide is also involved in the pathogenesis of vascular, inflammatory and fibrotic diseases. In particular, many pathological conditions that share an inflammatory component, such as atherosclerosis, pulmonary hypertension [1], [3], sepsis [4], lung diseases [5] and carcinomas [6], show elevated ET-1 levels, probably due to an alteration of the vascular structure with activation/accumulation of inflammatory cells.
The last findings from our group showed the expression of ET-1 and ECE-1 on isolated human PMNs [7] and on PMNs, MØs and mast cells in human inflammated tissues [8], [9], implying a much broader role for this peptide than just vasoactivity. ET-1 participates in the starting and development of inflammatory reaction. Moreover, as a chemotactic factor for MØs [10], it induces leukocyte rolling and adherence to endothelial cells, by enhancing the expression of adhesion molecules through a predominantly ETA receptor-mediated mechanism [11]. Finally, the peptide stimulates the production of inflammatory mediators, like cytokines and growth factors such as the vascular endothelial growth factor (VEGF) [12].
Therefore, the present work was aimed to evaluate for the first time the expression of ET-1 receptors in freshly isolated PMNs and MØs using a more direct approach (by immunofluorescence techniques) than the one present in the literature where up to know the presence of ET receptors in PMNs and MØs has been detected only in an indirect manner. Our data confirm the hypothesis that inflammatory cells present ETA receptor and that, consequently, can be directly activated by ET-1.
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Cell culture
The U373, human astrocytoma cell line, was grown in the DMEM (Dulbecco's Modified Eagle's Medium) (Sigma-Aldrich, St. Louis, MO, USA) supplemented with 10% fetal calf serum (FCS) (Sigma), 2 mM l-glutamine, penicillin–streptomycin (10,000 U/ml) and incubated in a humidified 5% CO2 atmosphere at 37 °C in 25 cm2 flasks.
Isolation and treatment of PMNs and monocytes
Human PMNs and lymphomonocytes (PBMCs) were separated from heparinized venous human peripheral blood and were obtained by density gradient Ficoll-Hypaque (Amersham Pharmacia
Results and discussion
In our previous studies we have demonstrated the wide distribution of ET-1 [8] and ECE-1 [9] in inflamed tissues and that this positivity was due to the presence of inflammatory cells such as PMNs, PBMCs and MØs in the tissue.
Furthermore, our group was also able to detect the presence of prepro-ET-1 mRNA in isolated PMNs and to quantify the release of the mature peptide after appropriate stimulation [7].
Thus, as a continuation of our work, this current study evaluates the presence of ET
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Long-term endothelin receptor antagonism attenuates coronary plaque progression in patients with early atherosclerosis
2013, International Journal of CardiologyCitation Excerpt :ETA receptors are expressed on inflammatory cells such as neutrophiles and macrophages. These cells play a key role in vascular dysfunction and inflammation via the possible formation of an autocrine loop between endothelin-1 and ETA receptor [33]. ET-1 promotes macrophage foam cell formation possibly via increased degradation of ATP-binding cassette transporter G1 (ABC G1) which mediates the net mass efflux of cholesterol to mature high density lipoprotein [34].
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2020, ToxinsA Promising Candidate: Heparin-Binding Protein Steps onto the Stage of Sepsis Prediction
2019, Journal of Immunology Research
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These authors contributed equally to the study.