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      Unidirectional fluxes of monovalent ions in human erythrocytes compared with lymphoid U937 cells: Transient processes after stopping the sodium pump and in response to osmotic challenge

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          Abstract

          Recently, we have developed software that allows, using a minimum of required experimental data, to find the characteristics of ion homeostasis and a list of all unidirectional fluxes of monovalent ions through the main pathways in the cell membrane both in a balanced state and during the transient processes. Our approach has been successfully validated in human proliferating lymphoid U937 cells during transient processes after stopping the Na/K pump by ouabain and for staurosporine-induced apoptosis. In present study, we used this approach to find the characteristics of ion homeostasis and the monovalent ion fluxes through the cell membrane of human erythrocytes in a resting state and during the transient processes after stopping the Na/K pump with ouabain and in response to osmotic challenge. Due to their physiological significance, erythrocytes remain the object of numerous studies, both experimental and computational methods. Calculations showed that, under physiological conditions, the K + fluxes through electrodiffusion channels in the entire erythrocyte ion balance is small compared to the fluxes through the Na/K pump and cation–chloride cotransporters. The proposed computer program well predicts the dynamics of the erythrocyte ion balance disorders after stopping the Na/K pump with ouabain. In full accordance with predictions, transient processes in human erythrocytes are much slower than in proliferating cells such as lymphoid U937 cells. Comparison of real changes in the distribution of monovalent ions under osmotic challenge with the calculated ones indicates a change in the parameters of the ion transport pathways through the plasma membrane of erythrocytes in this case. The proposed approach may be useful in studying the mechanisms of various erythrocyte dysfunctions.

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          Red blood cell dysfunction: a new player in cardiovascular disease

          The primary role of red blood cells (RBCs) is to transport oxygen to the tissues and carbon dioxide to the lungs. However, emerging evidence suggests an important role of the RBC beyond being just a passive carrier of the respiratory gases. The RBCs are of importance for redox balance and are actively involved in the regulation of vascular tone, especially during hypoxic and ischaemic conditions by the release of nitric oxide (NO) bioactivity and adenosine triphosphate. The role of the RBC has gained further interest after recent discoveries demonstrating a markedly altered function of the cell in several pathological conditions. Such alterations include increased adhesion capability, increased formation of reactive oxygen species as well as altered protein content and enzymatic activities. Beyond signalling increased oxidative stress, the altered function of RBCs is characterized by reduced export of NO bioactivity regulated by increased arginase activity. Of further importance, the altered function of RBCs has important implications for several cardiovascular disease conditions. RBCs have been shown to induce endothelial dysfunction and to increase cardiac injury during ischaemia-reperfusion in diabetes mellitus. Finally, this new knowledge has led to novel therapeutic possibilities to intervene against cardiovascular disease by targeting signalling in the RBC. These novel data open up an entirely new view on the underlying pathophysiological mechanisms behind the cardiovascular disease processes in diabetes mellitus mediated by the RBC. This review highlights the current knowledge regarding the role of RBCs in cardiovascular regulation with focus on their importance for cardiovascular dysfunction in pathological conditions and therapeutic possibilities for targeting RBCs in cardiovascular disease.
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            Red Blood Cell Passage of Small Capillaries Is Associated with Transient Ca 2+ -mediated Adaptations

            When red blood cells (RBCs) pass constrictions or small capillaries they need to pass apertures falling well below their own cross section size. We used different means of mechanical stimulations (hypoosmotic swelling, local mechanical stimulation, passing through microfluidic constrictions) to observe cellular responses of human RBCs in terms of intracellular Ca2+-signaling by confocal microscopy of Fluo-4 loaded RBCs. We were able to confirm our in vitro results in a mouse dorsal skinfold chamber model showing a transiently increased intracellular Ca2+ when RBCs were passing through small capillaries in vivo. Furthermore, we performed the above-mentioned in vitro experiments as well as measurements of RBCs filterability under various pharmacological manipulations (GsMTx-4, TRAM-34) to explore the molecular mechanism of the Ca2+-signaling. Based on these experiments we conclude that mechanical stimulation of RBCs activates mechano-sensitive channels most likely Piezo1. This channel activity allows Ca2+ to enter the cell, leading to a transient activation of the Gardos-channel associated with K+, Cl−, and water loss, i.e., with a transient volume adaptation facilitating the passage of the RBCs through the constriction.
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              Disorders of erythrocyte hydration.

              The erythrocyte contains a network of pathways that regulate salt and water content in the face of extracellular and intracellular osmotic perturbations. This allows the erythrocyte to maintain a narrow range of cell hemoglobin concentration, a process critical for normal red blood cell function and survival. Primary disorders that perturb volume homeostasis jeopardize the erythrocyte and may lead to its premature destruction. These disorders are marked by clinical, laboratory, and physiologic heterogeneity. Recent studies have revealed that these disorders are also marked by genetic heterogeneity. They have implicated roles for several proteins, PIEZO1, a mammalian mechanosensory protein; GLUT1, the glucose transporter; SLC4A1, the anion transporter; RhAG, the Rh-associated glycoprotein; KCNN4, the Gardos channel; and ABCB6, an adenosine triphosphate-binding cassette family member, in the maintenance of erythrocyte volume homeostasis. Secondary disorders of erythrocyte hydration include sickle cell disease, thalassemia, hemoglobin CC, and hereditary spherocytosis, where cellular dehydration may be a significant contributor to disease pathology and clinical complications. Understanding the pathways regulating erythrocyte water and solute content may reveal innovative strategies to maintain normal volume in disorders associated with primary or secondary cellular dehydration. These mechanisms will serve as a paradigm for other cells and may reveal new therapeutic targets for disease prevention and treatment beyond the erythrocyte.
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                Author and article information

                Contributors
                Role: Formal analysisRole: InvestigationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: Investigation
                Role: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draft
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                PLOS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                4 May 2023
                2023
                : 18
                : 5
                : e0285185
                Affiliations
                [001] Institute of Cytology, Russian Academy of Sciences, St-Petersburg, Russia
                Griffith University Menzies Health Institute Queensland, AUSTRALIA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0001-9693-0779
                https://orcid.org/0000-0002-1858-6738
                Article
                PONE-D-22-33351
                10.1371/journal.pone.0285185
                10159352
                37141334
                24ce3df1-38c4-4af8-a3e1-59aa10c6bb1c
                © 2023 Yurinskaya et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 5 December 2022
                : 11 April 2023
                Page count
                Figures: 3, Tables: 3, Pages: 18
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100012190, Ministry of Science and Higher Education of the Russian Federation;
                Award ID: Agreement № 075-15-2021-1075, signed 28 September 2021, local identifier 415/21–23
                This research was funded by a grant from the Ministry of Science and Higher Education of the Russian Federation (Agreement № 075-15-2021-1075, signed 28 September 2021, local identifier 415/21–23).
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Blood Cells
                Red Blood Cells
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Cell Membranes
                Biology and Life Sciences
                Physiology
                Physiological Processes
                Homeostasis
                Biology and Life Sciences
                Biophysics
                Ion Transport
                Physical Sciences
                Physics
                Biophysics
                Ion Transport
                Physical Sciences
                Chemistry
                Physical Chemistry
                Ions
                Physical Sciences
                Materials Science
                Material Properties
                Permeability
                Biology and Life Sciences
                Physiology
                Electrophysiology
                Membrane Potential
                Physical Sciences
                Chemistry
                Chemical Compounds
                Organic Compounds
                Carbohydrates
                Disaccharides
                Sucrose
                Physical Sciences
                Chemistry
                Organic Chemistry
                Organic Compounds
                Carbohydrates
                Disaccharides
                Sucrose
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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