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      Increase in Red Blood Cell-Nitric Oxide Synthase Dependent Nitric Oxide Production during Red Blood Cell Aging in Health and Disease: A Study on Age Dependent Changes of Rheologic and Enzymatic Properties in Red Blood Cells

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          Abstract

          Aim

          To investigate RBC-NOS dependent NO signaling during in vivo RBC aging in health and disease.

          Method

          RBC from fifteen healthy volunteers (HC) and four patients with type 2 diabetes mellitus (DM) were separated in seven subpopulations by Percoll density gradient centrifugation.

          Results

          The proportion of old RBC was significantly higher in DM compared to HC. In both groups, in vivo aging was marked by changes in RBC shape and decreased cell volume. RBC nitrite, as marker for NO, was higher in DM and increased in both HC and DM during aging. RBC deformability was lower in DM and significantly decreased in old compared to young RBC in both HC and DM. RBC-NOS Serine 1177 phosphorylation, indicating enzyme activation, increased during aging in both HC and DM. Arginase I activity remained unchanged during aging in HC. In DM, arginase I activity was significantly higher in young RBC compared to HC but decreased during aging. In HC, concentration of L-arginine, the substrate of RBC-NOS and arginase I, significantly dropped from young to old RBC. In DM, L-arginine concentration was significantly higher in young RBC compared to HC and significantly decreased during aging. In blood from healthy subjects, RBC-NOS activation was additionally inhibited by N 5-(1-iminoethyl)-L-Ornithine dihydrochloride which decreased RBC nitrite, and impaired RBC deformability of all but the oldest RBC subpopulation.

          Conclusion

          This study first-time showed highest RBC-NOS activation and NO production in old RBC, possibly to counteract the negative impact of cell shrinkage on RBC deformability. This was even more pronounced in DM. It is further suggested that highly produced NO only insufficiently affects cell function of old RBC maybe because of isolated RBC-NOS in old RBC thus decreasing NO bioavailability. Thus, increasing NO availability may improve RBC function and may extend cell life span in old RBC.

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          Most cited references65

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          S-nitrosohaemoglobin: a dynamic activity of blood involved in vascular control.

          A dynamic cycle exists in which haemoglobin is S-nitrosylated in the lung when red blood cells are oxygenated, and the NO group is released during arterial-venous transit. The vasoactivity of S-nitrosohaemoglobin is promoted by the erythrocytic export of S-nitrosothiols. These findings highlight newly discovered allosteric and electronic properties of haemoglobin that appear to be involved in the control of blood pressure and which may facilitate efficient delivery of oxygen to tissues. The role of S-nitrosohaemoglobin in the transduction of NO-related activities may have therapeutic applications.
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            Arginase: a critical regulator of nitric oxide synthesis and vascular function.

            1. Arginase is the focal enzyme of the urea cycle hydrolysing L-arginine to urea and L-ornithine. Emerging studies have identified arginase in the vasculature and have implicated this enzyme in the regulation of nitric oxide (NO) synthesis and the development of vascular disease. 2. Arginase inhibits the production of NO via several potential mechanisms, including competition with NO synthase (NOS) for the substrate L-arginine, uncoupling of NOS resulting in the generation of the NO scavenger, superoxide and peroxynitrite, repression of the translation and stability of inducible NOS protein, inhibition of inducible NOS activity via the generation of urea and by sensitization of NOS to its endogenous inhibitor asymmetric dimethyl-L-arginine. 3. Upregulation of arginase inhibits endothelial NOS-mediated NO synthesis and may contribute to endothelial dysfunction in hypertension, ageing, ischaemia-reperfusion and diabetes. 4. Arginase also redirects the metabolism of L-arginine to L-ornithine and the formation of polyamines and L-proline, which are essential for smooth muscle cell growth and collagen synthesis. Therefore, the induction of arginase may also promote aberrant vessel wall remodelling and neointima formation. 5. Arginase represents a promising novel therapeutic target that may reverse endothelial and smooth muscle cell dysfunction and prevent vascular disease.
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              Red blood cells express a functional endothelial nitric oxide synthase.

              The synthesis of nitric oxide (NO) in the circulation has been attributed exclusively to the vascular endothelium. Red blood cells (RBCs) have been demonstrated to carry a nonfunctional NO synthase (NOS) and, due to their huge hemoglobin content, have been assumed to metabolize large quantities of NO. More recently, however, RBCs have been identified to reversibly bind, transport, and release NO within the cardiovascular system. We now provide evidence that RBCs from humans express an active and functional endothelial-type NOS (eNOS), which is localized in the plasma membrane and the cytoplasm of RBCs. This NOS is regulated by its substrate L-arginine, by calcium, and by phosphorylation via PI3 kinase. RBC-NOS activity regulates deformability of RBC membrane and inhibits activation of platelets. The NOS-dependent conversion of L-arginine in RBCs is comparable to that of cultured human endothelial cells. RBCs in eNOS-/- mice in contrast to wild-type mice lack NOS protein and activity, strengthening the evidence of an eNOS in RBCs. These data show an eNOS-like protein and activity in RBCs serving regulatory functions in RBCs and platelets, which may stimulate new approaches in the treatment of NO deficiency states inherent to several vascular and hematologic diseases.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                22 April 2015
                2015
                : 10
                : 4
                : e0125206
                Affiliations
                [001]Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, Cologne, Germany
                University Medical Center Utrecht, NETHERLANDS
                Author notes

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

                Conceived and designed the experiments: MG DAB CB. Performed the experiments: MG DAB. Analyzed the data: MG DAB. Contributed reagents/materials/analysis tools: MG WB CB. Wrote the paper: MG DAB WB CB.

                Article
                PONE-D-14-56531
                10.1371/journal.pone.0125206
                4406474
                25902315
                279f7972-7ca7-4104-8cb0-efa32e2aae4a
                Copyright @ 2015

                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
                : 17 December 2014
                : 11 March 2015
                Page count
                Figures: 8, Tables: 0, Pages: 23
                Funding
                The authors have no support or funding to report.
                Categories
                Research Article
                Custom metadata
                Due to legal restrictions, raw data are available upon request from M.Grau@ 123456dshs-koeln.de .

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                Uncategorized

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