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      Connection between Telomerase Activity in PBMC and Markers of Inflammation and Endothelial Dysfunction in Patients with Metabolic Syndrome

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          Abstract

          Metabolic syndrome (MS) is a constellation of metabolic derangements associated with vascular endothelial dysfunction and oxidative stress and is widely regarded as an inflammatory condition, accompanied by an increased risk for cardiovascular disease. The present study tried to investigate the implications of telomerase activity with inflammation and impaired endothelial function in patients with metabolic syndrome. Telomerase activity in circulating peripheral blood mononuclear cells (PBMC), TNF-α, IL-6 and ADMA were monitored in 39 patients with MS and 20 age and sex-matched healthy volunteers. Telomerase activity in PBMC, TNF-α, IL-6 and ADMA were all significantly elevated in patients with MS compared to healthy volunteers. PBMC telomerase was negatively correlated with HDL and positively correlated with ADMA, while no association between TNF-α and IL-6 was observed. IL-6 was increasing with increasing systolic pressure both in the patients with MS and in the healthy volunteers, while smoking and diabetes were positively correlated with IL-6 only in the patients' group. In conclusion, in patients with MS characterised by a strong dyslipidemic profile and low diabetes prevalence, significant telomerase activity was detected in circulating PBMC, along with elevated markers of inflammation and endothelial dysfunction. These findings suggest a prolonged activity of inflammatory cells in the studied state of this metabolic disorder that could represent a contributory pathway in the pathogenesis of atherosclerosis.

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          Asymmetric Dimethylarginine (ADMA): A Novel Risk Factor for Endothelial Dysfunction : Its Role in Hypercholesterolemia

          Background —Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide (NO) synthase. Because endothelial NO elaboration is impaired in hypercholesterolemia, we investigated whether plasma concentrations of ADMA are elevated in young, clinically asymptomatic hypercholesterolemic adults. We further studied whether such elevation of ADMA levels was correlated with impaired endothelium-dependent, NO-mediated vasodilation and urinary nitrate excretion. In a randomized, double-blind, placebo-controlled study, we investigated whether these changes could be reversed with exogenous l -arginine. Methods and Results —We measured plasma levels of l -arginine, ADMA, and symmetrical dimethylarginine (SDMA) by high-performance liquid chromatography in 49 hypercholesterolemic (HC) and 31 normocholesterolemic (NC) humans. In 8 HC subjects, endothelium-dependent forearm vasodilation was assessed before and after an intravenous infusion of l -arginine or placebo and compared with 8 NC control subjects. ADMA levels were significantly elevated by >100% (2.17±0.15 versus 1.03±0.09 μmol/L; P <0.05) in HC subjects compared with NC adults. l -Arginine levels were similar, resulting in a significantly decreased l -arginine/ADMA ratio in HC subjects (27.7±2.4 versus 55.7±5.4; P <0.05). In 8 HC subjects, intravenous infusion of l -arginine significantly increased the l -arginine/ADMA ratio and normalized endothelium-dependent vasodilation and urinary nitrate excretion. ADMA levels were inversely correlated with endothelium-mediated vasodilation ( R =0.762, P <0.01) and urinary nitrate excretion rates ( R =0.534, P <0.01). Conclusions —We find that ADMA is elevated in young HC individuals. Elevation of ADMA is associated with impaired endothelium-dependent vasodilation and reduced urinary nitrate excretion. This abnormality is reversed by administration of l -arginine. ADMA may be a novel risk factor for endothelial dysfunction in humans.
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            Nitric oxide: an endogenous modulator of leukocyte adhesion.

            The objective of this study was to determine whether endogenous nitric oxide (NO) inhibits leukocyte adhesion to vascular endothelium. This was accomplished by superfusing a cat mesenteric preparation with inhibitors of NO production, NG-monomethyl-L-arginine (L-NMMA) or NG-nitro-L-arginine methyl ester (L-NAME), and observing single (30-microns diameter) venules by intravital video microscopy. Thirty minutes into the superfusion period the number of adherent and emigrated leukocytes, the erythrocyte velocity, and the venular diameter were measured; venular blood flow and shear rate were calculated from the measured parameters. The contribution of the leukocyte adhesion glycoprotein CD11/CD18 was determined using the CD18-specific monoclonal antibody IB4. Both inhibitors of NO production increased leukocyte adherence more than 15-fold. Leukocyte emigration was also enhanced, whereas venular shear rate was reduced by nearly half. Antibody IB4 abolished the leukocyte adhesion induced by L-NMMA and L-NAME. Incubation of isolated cat neutrophils with L-NMMA, but not L-NAME, resulted in direct upregulation of CD11/CD18 as assessed by flow cytometry. Decrements in venular shear rate induced by partial occlusion of the superior mesenteric artery in untreated animals revealed that only a minor component of L-NAME-induced leukocyte adhesion was shear rate-dependent. The L-NAME-induced adhesion was inhibited by L-arginine but not D-arginine. These data suggest that endothelium-derived NO may be an important endogenous modulator of leukocyte adherence and that impairment of NO production results in a pattern of leukocyte adhesion and emigration that is characteristic of acute inflammation.
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              Estrogen and mechanisms of vascular protection.

              Estrogen has antiinflammatory and vasoprotective effects when administered to young women or experimental animals that appear to be converted to proinflammatory and vasotoxic effects in older subjects, particularly those that have been hormone free for long periods. Clinical studies have raised many important questions about the vascular effects of estrogen that cannot easily be answered in human subjects. Here we review cellular/molecular mechanisms by which estrogen modulates injury-induced inflammation, growth factor expression, and oxidative stress in arteries and isolated vascular smooth muscle cells, with emphasis on the role of estrogen receptors and the nuclear factor-kappaB (NFkappaB) signaling pathway, as well as evidence that these protective mechanisms are lost in aging subjects.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                25 April 2012
                : 7
                : 4
                : e35739
                Affiliations
                [1 ]Second Cardiology Department, Amalia Fleming General Hospital, Athens, Attiki, Greece
                [2 ]Cardiology Division, General Hospital of Karditsa, Terma Tavropou, Karditsa, Greece
                [3 ]A' Pathology Department, Amalia Fleming General Hospital, Athens, Attiki, Greece
                [4 ]Cytogenetic Unit, Sismanoglio General Hospital, Athens, Attiki, Greece
                [5 ]ESEAP - Greek Proficiency testing scheme (for Laboratory Medicine), Diamedica Laboratories Department SA, Athens, Attiki, Greece
                [6 ]Department of Biochemistry, Hellenic Pasteur Institute, Ampelokipi, Athens, Greece
                [7 ]Department of Biochemistry and Biotechnology, University of Thessaly, Larisa, Greece
                [8 ]General Chemical State Laboratory of Greece, Athens, Attiki, Greece
                University of Tor Vergata, Italy
                Author notes

                Conceived and designed the experiments: ER KT CT. Performed the experiments: KT EK SK AH AM CT. Analyzed the data: CT IK MN GM DK. Contributed reagents/materials/analysis tools: ER AH DK. Wrote the paper: CT KT. Provided patients and controls: ER KT EK GM.

                Article
                PONE-D-11-25792
                10.1371/journal.pone.0035739
                3338458
                22558213
                44ef500b-6c23-4cf8-9b09-5af01a6cc726
                Rentoukas 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
                : 16 December 2011
                : 20 March 2012
                Page count
                Pages: 4
                Categories
                Research Article
                Biology
                Genomics
                Chromosome Biology
                Telomeres
                Immunology
                Immunity
                Inflammation
                Molecular Cell Biology
                Cellular Types
                Endothelial Cells
                Chromosome Biology
                Telomeres
                Medicine
                Cardiovascular
                Clinical Immunology
                Immunity
                Inflammation
                Metabolic Disorders

                Uncategorized
                Uncategorized

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