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      Endothelial nitric oxide synthase gene polymorphisms in patients with slow coronary flow

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          Abstract

          Background and aims

          The aim of this study was to explore potential associations of the intron 4 variable number of tandem repeats (VNTR) and E298A polymorphisms of the endothelial nitric oxide synthase (eNOS) gene with slow coronary flow (SCF). The association between plasma nitrate and nitrite (NO x ) concentrations and eNOS gene polymorphisms was also assessed.

          Materials and methods

          The intron 4 VNTR and E298A polymorphisms of the eNOS gene were evaluated in the isolated DNA blood samples obtained from the SCF patient group ( n = 30) and healthy group consisted of age- and sex-matched controls ( n = 61).

          Results

          Plasma NO x level was significantly lower in patients with SCF than in controls. In addition, patients with SCF have significantly lower nitric oxide levels than control subjects within each genotype variants. The allele and genotyped frequencies of the eNOS intron 4 VNTR and E298A polymorphisms were similar between patients with SCF and the controls. Plasma NO x concentrations with respect to the relevant genotypes were found insignificant.

          Discussion and conclusion

          Plasma NO x is lower in patients with SCF than in healthy subjects. Our findings may suggest the lack of association between intron 4 VNTR and E298A polymorphisms of the eNOS gene and SCF.

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          Most cited references38

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          TIMI frame count: a quantitative method of assessing coronary artery flow.

          Although the Thrombolysis in Myocardial Infarction (TIMI) flow grade is valuable and widely used qualitative measure in angiographic trials, it is limited by its subjective and categorical nature. In normal patients and patients with acute myocardial infarction (MI) (TIMI 4), the number of cineframes needed for dye to reach standardized distal landmarks was counted to objectively assess an index of coronary blood flow as a continuous variable. The TIMI frame-counting method was reproducible (mean absolute difference between two injections, 4.7 +/- 3.9 frames, n=85). In 78 consecutive normal arteries, the left anterior descending coronary artery (LAD) TIMI frame count (36.2 +/- 2.6 frames) was 1.7 times longer than the mean of the right coronary artery (20.4 +/- 3.0) and circumflex counts (22.2 +/- 4.1, P < .001 for either versus LAD). Therefore, the longer LAD frame counts were corrected by dividing by 1.7 to derive the corrected TIMI frame count (CTFC). The mean CTFC in culprit arteries 90 minutes after thrombolytic administration followed a continuous unimodal distribution (there were not subpopulations of slow and fast flow) with a mean value of 39.2 +/- 20.0 frames, which improved to 31.7 +/- 12.9 frames by 18 to 36 hours (P < .001). No correlation existed between improvements in CTFCs and changes in minimum lumen diameter (r=-.05, P=.59). The mean 90-minute CTFC among nonculprit arteries (25.5 +/- 9.8) was significantly higher (flow was slower) compared with arteries with normal flow in the absence of acute MI (21.0 +/- 3.1, P < .001) but improved to that of normal arteries by 1 day after thrombolysis (21.7 +/- 7.1, P=NS). The CTFC is a simple, reproducible, objective and quantitative index of coronary flow that allows standardization of TIMI flow grades and facilitates comparisons of angiographic end points between trials. Disordered resistance vessel function may account in part for reductions in flow in the early hours after thrombolysis.
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            Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines.

            To test the hypothesis that nitric oxide (NO) limits endothelial activation, we treated cytokine-stimulated human saphenous vein endothelial cells with several NO donors and assessed their effects on the inducible expression of vascular cell adhesion molecule-1 (VCAM-1). In a concentration-dependent manner, NO inhibited interleukin (IL)-1 alpha-stimulated VCAM-1 expression by 35-55% as determined by cell surface enzyme immunoassays and flow cytometry. This inhibition was paralleled by reduced monocyte adhesion to endothelial monolayers in nonstatic assays, was unaffected by cGMP analogues, and was quantitatively similar after stimulation by either IL-1 alpha, IL-1 beta, IL-4, tumor necrosis factor (TNF alpha), or bacterial lipopolysaccharide. NO also decreased the endothelial expression of other leukocyte adhesion molecules (E-selectin and to a lesser extent, intercellular adhesion molecule-1) and secretable cytokines (IL-6 and IL-8). Inhibition of endogenous NO production by L-N-monomethyl-arginine also induced the expression of VCAM-1, but did not augment cytokine-induced VCAM-1 expression. Nuclear run-on assays, transfection studies using various VCAM-1 promoter reporter gene constructs, and electrophoretic mobility shift assays indicated that NO represses VCAM-1 gene transcription, in part, by inhibiting NF-kappa B. We propose that NO's ability to limit endothelial activation and inhibit monocyte adhesion may contribute to some of its antiatherogenic and antiinflammatory properties within the vessel wall.
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              Nitric oxide: an endogenous modulator of leukocyte adhesion.

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                Author and article information

                Journal
                imas
                IMAS
                Interventional Medicine and Applied Science
                Interventional Medicine and Applied Science
                Akadémiai Kiadó (Budapest )
                2061-1617
                2061-5094
                22 September 2017
                September 2017
                : 9
                : 3
                : 117-122
                Affiliations
                [ 1 ]Department of Biochemistry, Acıbadem University School of Medicine , İstanbul, Turkey
                [ 2 ]Department of Cardiology, Başkent University School of Medicine , Ankara, Turkey
                [ 3 ]Department of Medical Biology and Genetics, Başkent University School of Medicine , Ankara, Turkey
                [ 4 ]Department of Cardiology, Acıbadem University , İstanbul, Turkey
                Author notes
                [* ]Corresponding author: Nurzen Sezgin; Department of Biochemistry, Acıbadem Adana Hospital, Acıbadem University School of Medicine, Doseme Mh, Cumhuriyet Cd, No:66, 01130 Seyhan, Adana, Istanbul, Turkey; Phone: +90 322 455 4317; Fax: +90 322 455 4474; E-mail: nurzensezgin@ 123456hotmail.com
                Article
                10.1556/1646.9.2017.17
                5700696
                29201435
                37b0af28-e28d-472d-bc16-7a8abffe3ce0
                © 2017 The Author(s)

                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 for non-commercial purposes, provided the original author and source are credited.

                History
                : 16 March 2017
                : 21 April 2017
                Page count
                Figures: 2, Tables: 3, Equations: 0, References: 32, Pages: 13
                Funding
                Funding sources: No financial support was received for this study.
                Categories
                ORIGINAL PAPER

                Medicine,Immunology,Health & Social care,Microbiology & Virology,Infectious disease & Microbiology
                slow coronary flow,nitric oxide,endothelial nitric oxide synthase gene polymorphism,coronary disease,endothelial function

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