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      Is Open Access

      Cardiovascular Changes in Atherosclerotic ApoE-Deficient Mice Exposed to Co60 (γ) Radiation

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          Abstract

          Background

          There is evidence for a role of ionizing radiation in cardiovascular diseases. The goal of this work was to identify changes in oxidative and nitrative stress pathways and the status of the endothelinergic system during progression of atherosclerosis in ApoE-deficient mice after single and repeated exposure to ionizing radiation.

          Methods and Results

          B6.129P2-ApoE tmlUnc mice on a low-fat diet were acutely exposed (whole body) to Co60 (γ) (single dose 0, 0.5, and 2 Gy) at a dose rate of 36.32 cGy/min, or repeatedly (cumulative dose 0 and 2 Gy) at a dose-rate of 0.1 cGy/min for 5 d/wk, over a period of 4 weeks. Biological endpoints were investigated after 3–6 months of recovery post-radiation. The nitrative stress marker 3-nitrotyrosine and the vasoregulator peptides endothelin-1 and endothelin-3 in plasma were increased (p<0.05) in a dose-dependent manner 3–6 months after acute or chronic exposure to radiation. The oxidative stress marker 8-isoprostane was not affected by radiation, while plasma 8-hydroxydeoxyguanosine and L-3,4-dihydroxyphenylalanine decreased (p<0.05) after treatment. At 2Gy radiation dose, serum cholesterol was increased (p = 0.008) relative to controls. Percent lesion area increased (p = 0.005) with age of animal, but not with radiation treatment.

          Conclusions

          Our observations are consistent with persistent nitrative stress and activation of the endothelinergic system in ApoE−/− mice after low-level ionizing radiation exposures. These mechanisms are known factors in the progression of atherosclerosis and other cardiovascular diseases.

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          Most cited references 52

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          Nitric oxide and peroxynitrite in health and disease.

          The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.
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            Apolipoprotein E: cholesterol transport protein with expanding role in cell biology.

             R Mahley (1988)
            Apolipoprotein E is a plasma protein that serves as a ligand for low density lipoprotein receptors and, through its interaction with these receptors, participates in the transport of cholesterol and other lipids among various cells of the body. A mutant form of apolipoprotein E that is defective in binding to low density lipoprotein receptors is associated with familial type III hyperlipoproteinemia, a genetic disorder characterized by elevated plasma cholesterol levels and accelerated coronary artery disease. Apolipoprotein E is synthesized in various organs, including liver, brain, spleen, and kidney, and is present in high concentrations in interstitial fluid, where it appears to participate in cholesterol redistribution from cells with excess cholesterol to those requiring cholesterol. Apolipo-protein E also appears to be involved in the repair response to tissue injury; for example, markedly increased amounts of apolipoprotein E are found at sites of peripheral nerve injury and regeneration. Other functions of apolipoprotein E, unrelated to lipid transport, are becoming known, including immunoregulation and modulation of cell growth and differentiation.
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              Endothelial function and oxidative stress in cardiovascular diseases.

              The vascular endothelium is involved in the release of various vasodilators, including nitric oxide (NO), prostacyclin and endothelium-derived hyperpolarizing factor, as well as vasoconstrictors. NO plays an important role in the regulation of vascular tone, inhibition of platelet aggregation, and suppression of smooth muscle cell proliferation. Endothelial dysfunction is the initial step in the pathogenesis of atherosclerosis. Cardiovascular diseases are associated with endothelial dysfunction. It is well known that the grade of endothelial function is a predictor of cardiovascular outcomes. Oxidative stress plays an important role in the pathogenesis and development of cardiovascular diseases. Several mechanisms contribute to impairment of endothelial function. An imbalance of reduced production of NO or increased production of reactive oxygen species, mainly superoxide, may promote endothelial dysfunction. One mechanism by which endothelium-dependent vasodilation is impaired is an increase in oxidative stress that inactivates NO. This review focuses on recent findings and interaction between endothelial function and oxidative stress in cardiovascular diseases.
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                Author and article information

                Affiliations
                [1 ]Analytical Biochemistry and Proteomics Laboratory, Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada
                [2 ]Inhalation Toxicology Laboratory, Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada
                [3 ]Radiological Protection Research and Instrumentation Branch, Atomic Energy Canada Limited, Chalk River Laboratories, Chalk River, Ontario, Canada
                [4 ]Radiation Protection Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada
                [5 ]Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada
                Kagoshima University Graduate School of Medical and Dental Sciences, Japan
                Author notes

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

                Conceived and designed the experiments: PK RV HW RM MH AT SW. Performed the experiments: PK RV EB AS PG HW RM SW. Analyzed the data: PK RV EB AS SW. Wrote the paper: PK RV.

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                20 June 2013
                : 8
                : 6
                PONE-D-12-35331
                10.1371/journal.pone.0065486
                3688723
                23840332

                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.

                Counts
                Pages: 10
                Funding
                The work was supported by operational funds at Health Canada and AECL (Atomic Energy of Canada Limited). Outside of the investigators directly involved in the study, the institutional funders had no direct role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Biophysics
                Radiation Biophysics
                Radiation Effects
                Radiation Exposure
                Model Organisms
                Animal Models
                Mouse
                Chemistry
                Nuclear Chemistry
                Radiation Chemistry
                Medicine
                Cardiovascular
                Atherosclerosis
                Diagnostic Medicine
                Pathology
                General Pathology
                Biomarkers
                Oncology
                Basic Cancer Research
                Oxidative Damage
                Physics
                Biophysics
                Radiation Biophysics
                Radiation Effects
                Radiation Exposure
                Nuclear Physics
                Radiation
                Gamma Radiation

                Uncategorized

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