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      Impact of Superoxide Dismutase Mimetic AEOL 10150 on the Endothelin System of Fischer 344 Rats

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          Abstract

          Endothelin-1 is a potent vasoconstrictor and mitogenic peptide involved in the regulation of vasomotor tone and maintenance of blood pressure. Oxidative stress activates the endothelin system, and is implicated in pulmonary and cardiovascular diseases including hypertension, congestive heart failure, and atherosclerosis. Superoxide dismutase mimetics designed with the aim of treating diseases that involve reactive oxygen species in their pathophysiology may exert a hypotensive effect, but effects on the endothelin system are unknown. Our objective was to determine the effect of the superoxide dismutase mimetic AEOL 10150 on the basal endothelin system in vivo. Male Fischer-344 rats were injected subcutaneously with 0, 2 or 5 mg/kg body weight of AEOL 10150 in saline. Plasma oxidative stress markers and endothelins (bigET-1, ET-1, ET-2, ET-3) as well as lung and heart endothelin/nitric oxide system gene expressions were measured using HPLC-Coularray, HPLC-Fluorescence and RT-PCR respectively. AEOL 10150 reduced (p<0.05) the circulating levels of isoprostane (-25%) and 3-nitrotyrosine (-50%) measured in plasma 2h and 24h after treatment, confirming delivery of a physiologically-relevant dose and the potent antioxidant activity of the drug. The reduction in markers of oxidative stress coincided with sustained 24h decrease (p<0.05) of plasma levels of ET-1 (-50%) and ET-3 (-10%). Expression of preproET-1 and endothelin converting enzyme-1 mRNA were not altered significantly in the lungs. However preproET-1 (not significant) and ECE-1 mRNA (p<0.05) were increased (10–25%) in the heart. Changes in the lungs included decrease (p<0.05) of mRNA for the ET-1 clearance receptor ET B and the vasoconstriction-signaling ET A receptor (-30%), and an early surge of inducible nitric oxide synthase expression followed by sustained decrease (-40% after 24 hours). The results indicate that interception of the endogenous physiological flux of reactive nitrogen species and reactive oxygen species in rats impacts the endothelin/nitric oxide system, supporting a homeostatic relationship between those systems.

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          The role of oxidative stress in the pathophysiology of hypertension.

          Fabio Paoletto, Ramón Rodrigo, Jaime Madrigal-González (2011)
          Hypertension is considered to be the most important risk factor in the development of cardiovascular disease. An increasing body of evidence suggests that oxidative stress, which results in an excessive generation of reactive oxygen species (ROS), has a key role in the pathogenesis of hypertension. The modulation of the vasomotor system involves ROS as mediators of vasoconstriction induced by angiotensin II, endothelin-1 and urotensin-II, among others. The bioavailability of nitric oxide (NO), which is a major vasodilator, is highly dependent on the redox status. Under physiological conditions, low concentrations of intracellular ROS have an important role in the normal redox signaling maintaining vascular function and integrity. However, under pathophysiological conditions, increased levels of ROS contribute to vascular dysfunction and remodeling through oxidative damage. In human hypertension, an increase in the production of superoxide anions and hydrogen peroxide, a decrease in NO synthesis and a reduction in antioxidant bioavailability have been observed. In turn, antioxidants are reducing agents that can neutralize these oxidative and otherwise damaging biomolecules. The use of antioxidant vitamins, such as vitamins C and E, has gained considerable interest as protecting agents against vascular endothelial damage. Available data support the role of these vitamins as effective antioxidants that can counteract ROS effects. This review discusses the mechanisms involved in ROS generation, the role of oxidative stress in the pathogenesis of vascular damage in hypertension, and the possible therapeutic strategies that could prevent or treat this disorder.
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            Superoxide dismutases in the lung and human lung diseases.

            Vuokko Kinnula, James Crapo (2003)
            The lungs are directly exposed to higher oxygen concentrations than most other tissues. Increased oxidative stress is a significant part of the pathogenesis of obstructive lung diseases such as asthma and chronic obstructive pulmonary disease, parenchymal lung diseases (e.g., idiopathic pulmonary fibrosis and lung granulomatous diseases), and lung malignancies. Lung tissue is protected against these oxidants by a variety of antioxidant mechanisms among which the superoxide dismutases (SODs) are the only ones converting superoxide radicals to hydrogen peroxide. There are three SODs: cytosolic copper-zinc, mitochondrial manganese, and extracellular SODs. These enzymes have specific distributions and functions. Their importance in protecting lung tissue has been confirmed in transgenic and knockout animal studies. Relatively few studies have been conducted on these enzymes in the normal human lung or in human lung diseases. Most human studies suggest that there is induction of manganese SOD and, possibly, extracellular SOD during inflammatory, but not fibrotic, phases of parenchymal lung diseases and that both copper-zinc SOD and manganese SOD may be downregulated in asthmatic airways. Many previous antioxidant therapies have been disappointing, but newly characterized SOD mimetics are being shown to protect against oxidant-related lung disorders in animal models.
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              Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease?

              P Cernacek, Daniel D. Langleben, Brandon Stewart … (1991)
              To explore the role of endothelin-1, a potent endothelial-derived vasoconstrictor peptide, in pulmonary hypertension, by measuring its concentration in arterial and venous plasma. A survey, case series study. University-affiliated hospitals and outpatient clinics. Twenty-seven patients with pulmonary hypertension: 7 with primary, and 20 with secondary pulmonary hypertension of various causes. The control groups (n = 16) comprised 8 healthy volunteers and 8 patients with coronary artery disease but without evidence of pulmonary hypertension. Pulmonary artery pressure was markedly increased (94/43 +/- 23/13 mm Hg) in the patients with pulmonary hypertension. Venous plasma immunoreactive endothelin-1, measured by a specific radioimmunoassay, was significantly higher in patients with pulmonary hypertension (3.5 +/- 2.5 pg/mL, P less than 0.001) than in normal subjects (1.45 +/- 0.45 pg/mL), or patients with coronary disease (0.75 +/- 0.64 pg/mL). The arterial-to-venous ratio of immunoreactive endothelin-1 was significantly greater than unity in primary pulmonary hypertension (2.21 +/- 0.72, P = 0.01), whereas the patients with secondary pulmonary hypertension had a mean ratio not different from 1 (0.97 +/- 0.42). In contrast, the mean arterial-to-venous ratios were significantly less than unity in both control groups (0.59 +/- 0.35, and 0.54 +/- 0.64; P less than 0.02, for normal subjects and coronary disease patients, respectively), indicating a possible clearance of endothelin-1 across the healthy lung. Patient with pulmonary hypertension have substantial alterations in plasma immunoreactive endothelin-1, which may reflect changes in net release or clearance of endothelin-1 by the lung. In patients with primary pulmonary hypertension, the high levels in arterial compared with venous plasma suggest pulmonary production of endothelin-1, which may contribute to elevated pulmonary vascular resistance.
              Article 0 comments Cited 98 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Alfred S Lewin: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 18 March 2016
                Publication date Collection: 2016
                Volume: 11
                Issue: 3
                Electronic Location Identifier: e0151810
                Affiliations
                [1 ]Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
                [2 ]Environmental Health Science and Research Bureau, Environmental and Radiation Health Sciences Directorate, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada
                [3 ]National Jewish Health, Denver, Colorado, United States of America
                University of Florida, UNITED STATES
                Author notes

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

                Conceived and designed the experiments: PK JC RV. Performed the experiments: DG PK EB. Analyzed the data: DG PK ET CS EB JC RV. Contributed reagents/materials/analysis tools: PK JC RV. Wrote the paper: DG PK ET CS EB JC RV.

                Article
                Publisher ID: PONE-D-15-22147
                DOI: 10.1371/journal.pone.0151810
                PMC ID: 4798617
                PubMed ID: 26990293
                SO-VID: 19407ec9-b9be-4f3d-8445-b5be822d96b4
                Copyright © © 2016 Ganesh et al
                License:

                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
                Date received : 15 June 2015
                Date accepted : 4 March 2016
                Page count
                Figures: 5, Tables: 0, Pages: 14
                Funding
                Toxic Substance Research Initiative (Health Canada) RV, Genomic Research and Development Initiative (Health Canada) RV, and Clean Air Regulatory Agenda (Health Canada) RV. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Cardiovascular Anatomy
                Subject: Heart
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Cardiovascular Anatomy
                Subject: Heart
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Body Fluids
                Subject: Blood
                Subject: Blood Plasma
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Body Fluids
                Subject: Blood
                Subject: Blood Plasma
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Body Fluids
                Subject: Blood
                Subject: Blood Plasma
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Body Fluids
                Subject: Blood
                Subject: Blood Plasma
                Subject: Medicine and Health Sciences
                Subject: Hematology
                Subject: Blood
                Subject: Blood Plasma
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Antioxidants
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Oxidative Stress
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Enzymology
                Subject: Enzymes
                Subject: Dismutases
                Subject: Superoxide Dismutase
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Proteins
                Subject: Enzymes
                Subject: Dismutases
                Subject: Superoxide Dismutase
                Subject: Biology and Life Sciences
                Subject: Genetics
                Subject: Gene Expression
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Neurochemistry
                Subject: Neurochemicals
                Subject: Nitric Oxide
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Neurochemistry
                Subject: Neurochemicals
                Subject: Nitric Oxide
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Oxidative Damage
                Subject: Reactive Oxygen Species
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                Data Availability All relevant data are provided within the paper.

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