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      Low Paraoxonase 1 Arylesterase Activity and High von Willebrand Factor Levels are Associated with Severe Coronary Atherosclerosis in Patients with Non-Diabetic Stable Coronary Artery Disease

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          Abstract

          Background

          Paraoxonase 1 (PON1) activity and von Willebrand factor (VWF) release are associated with lesion initiation in atherosclerosis. Diabetes can complicate coronary artery disease (CAD) due to the production of advanced glycation end products. This study evaluated PON1 activity and VWF levels in non-post-acute coronary syndrome, stable CAD (SCAD) patients without diabetes.

          Material/Methods

          Non-diabetic SCAD patients and patients experiencing acute stress periods were selected (n=130). Forty-seven cases with normal coronary angiography and 50 healthy individuals served as controls. The non-diabetic SCAD group was then stratified into single-vessel lesions, multiple-vessel lesions, and mild or severe luminal stenosis according to the number and the degree of luminal stenoses. Serum PON1 paraoxonase and arylesterase activities, and plasma VWF levels were measured, as well as serum total cholesterol, total triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and apolipoprotein A1. PON1 arylesterase activity was detected with an ordinary chemistry system using a novel phenylacetate derivative.

          Results

          Both PON1 paraoxonase and arylesterase were lower in the non-diabetic SCAD group, but VWF levels were higher (versus controls, all P<0.001). PON1 paraoxonase activity (OR=0.991), PON1 arylesterase activity (OR=0.981), and VWF (OR 2.854) influenced SCAD in multiple logistic regression. Decreased PON1 arylesterase activity and increased VWF levels were associated with severe atherosclerosis in non-diabetic SCAD patients. We also observed a slight negative correlation between VWF and PON1 paraoxonase/arylesterase.

          Conclusions

          PON1 and VWF are detectable markers that may predict the severity of stenoses, ideally facilitating a non-diabetic SCAD diagnosis before the sudden onset of life-threatening symptoms.

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          Most cited references19

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          von Willebrand factor, endothelial dysfunction, and cardiovascular disease.

          U Vischer (2006)
          von Willebrand factor (VWF), a glycoprotein involved in arterial thrombus formation, is released into the circulation by secretion from endothelial cells. Plasma VWF levels are determined by genetic factors including ABO blood groups and VWF mutations, and by non-genetic factors including aging, impaired nitric oxide production, inflammation, free radical production and diabetes. Plasma VWF levels have been proposed as a risk factor for cardiovascular events. Although they are only weakly associated with the risk of coronary heart disease (CHD) in the general population, they are a more promising CHD risk factor in high-risk populations with previous cardiovascular events, diabetes or old age. However, is it still unclear whether VWF levels directly determine the rate and severity of arterial thrombus formation or whether they merely reflect alteration in other endothelial functions. The future status of VWF levels as a cardiovascular risk factor depends on additional studies on the genetic determinants of both VWF levels and cardiovascular outcomes. Further studies on VWF levels as a predictor of the risk of stroke (rather than CHD) in elderly or other high-risk population are also promising. Such studies could lead to the clinical use of plasma VWF levels to refine the estimation of the cardiovascular risk and of the expected benefit of antithrombotic agents.
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            The three-gene paraoxonase family: physiologic roles, actions and regulation.

            The paraoxonase (PON) gene family is composed of three members (PON1, PON2, PON3) that share considerable structural homology and are located adjacently on chromosome 7 in humans. By far the most-studied member is PON1, a high-density lipoprotein-associated esterase/lactonase, also endowed with the capacity to hydrolyze organophosphates, but all the three proteins prevent oxidative stress and fight inflammation. They therefore seem central to a wide variety of human illnesses, including atherosclerosis, diabetes mellitus, mental disorders and inflammatory bowel disease. The major goal of this review is to highlight the regulation of each of the paraoxonase components by diverse nutritional molecules and pharmacological agents as well as a number of pathophysiological events, such as oxidative stress and inflammation. Considerable and detailed cell-based studies and animal model experiments have been provided to allow a thorough scrutiny of PON modulation, which will increase our understanding and ability to target these genes in order to efficiently increase their transcriptional activity and decrease the risks of developing different disorders. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
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              Clinical and genetic association of serum paraoxonase and arylesterase activities with cardiovascular risk.

              Diminished serum paraoxonase and arylesterase activities (measures of paraoxonase-1 [PON-1] function) in humans have been linked to heightened systemic oxidative stress and atherosclerosis risk. The clinical prognostic use of measuring distinct PON-1 activities has not been established, and the genetic determinants of PON-1 activities are not known. We established analytically robust high-throughput assays for serum paraoxonase and arylesterase activities and measured these in 3668 stable subjects undergoing elective coronary angiography without acute coronary syndrome and were prospectively followed for major adverse cardiovascular events (MACE= death, myocardial infarction, stroke) over 3 years. Low serum arylesterase and paraoxonase activities were both associated with increased risk for MACE, with arylesterase activity showing greatest prognostic value (quartile 4 versus quartile 1; hazard ratio 2.63; 95% CI, 1.97-3.50; P<0.01). Arylesterase remained significant after adjusting for traditional risk factors, C-reactive protein, and creatinine clearance (hazard ratio, 2.20; 95% CI, 1.60-3.02; P<0.01), predicted future development of MACE in both primary and secondary prevention populations, and reclassified risk categories incrementally to traditional clinical variables. A genome-wide association study identified distinct single nucleotide polymorphisms within the PON-1 gene that were highly significantly associated with serum paraoxonase (1.18×10(-303)) or arylesterase (4.99×10(-116)) activity but these variants were not associated with either 3-year MACE risk in an angiographic cohort (n=2136) or history of either coronary artery disease or myocardial infarction in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis consortium (n≈80 000 subjects). Diminished serum arylesterase activity, but not the genetic determinants of PON-1 functional measures, provides incremental prognostic value and clinical reclassification of stable subjects at risk of developing MACE.
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                Author and article information

                Journal
                Med Sci Monit
                Med. Sci. Monit
                Medical Science Monitor
                Medical Science Monitor : International Medical Journal of Experimental and Clinical Research
                International Scientific Literature, Inc.
                1234-1010
                1643-3750
                2014
                25 November 2014
                : 20
                : 2421-2429
                Affiliations
                [1 ]Department of Clinical Laboratories, Ninth People’s Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China
                [2 ]Department of Cardiology, Ninth People’s Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China
                [3 ]Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
                Author notes
                Corresponding Authors: Lili Xu, e-mail: xu.lili3@ 123456zs-hospital.sh.cn and Fuxiang Chen, e-mial: chenfx@ 123456sjtu.edu.cn
                [A]

                Study Design

                [B]

                Data Collection

                [C]

                Statistical Analysis

                [D]

                Data Interpretation

                [E]

                Manuscript Preparation

                [F]

                Literature Search

                [G]

                Funds Collection

                Article
                890911
                10.12659/MSM.890911
                4254670
                25420483
                7106d8ff-d79b-4fbf-b9c3-8fb218cddd42
                © Med Sci Monit, 2014

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License

                History
                : 23 April 2014
                : 30 June 2014
                Categories
                Clinical Research

                aryldialkylphosphatase,bernard-soulier syndrome,cardiology

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