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      UCP-2 is involved in angiotensin-II-induced abdominal aortic aneurysm in apolipoprotein E-knockout mice

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          Abstract

          UCP-2 shows an important role in modulating of mitochondrial membrane potential and cell apoptosis. Whether or not UCP-2 could been a critical factor in preventing AAA formation is not known. We report that UCP-2 protein and mRNA expression were significantly higher in Ang-Ⅱ-induced AAA of mice. The incident rate of AAA in UCP-2 -/-ApoE -/- mice after Ang-Ⅱtreatment was higher than the rate in the UCP-2 +/+ApoE -/- mice. The abdominal aorta from UCP-2 -/-ApoE -/- mice showed the medial hypertrophy, fragmentation of elastic lamellas and depletion of α-SMA. The NADPH oxidase activity and level of MDA was significantly higher in UCP-2 -/-ApoE -/- mice than UCP-2 +/+ApoE -/- or WT mice. Besides, the SOD activity is increased in UCP-2 +/+ApoE -/- mice as compared with WT mice, whereas deficiency of UCP-2 decreased the increasing SOD activity in Ang-Ⅱ treated ApoE -/- mice. UCP-2 knockout up-regulated the MMP2 and MMP9 expression in aortic aneurysm. Ang-Ⅱ induced apoptosis of VSMCs was increased in UCP-2 -/-ApoE -/- mice. And the expression of eNOS in vascular tissue from UCP-2 -/-ApoE -/- mice is lower than WT and UCP-2 +/+ApoE -/- mice. This study provides a mechanism by which UCP-2, via anti-oxidants and anti-apoptosis, participates in the preventing of AAA formation.

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          Most cited references37

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          Abdominal aortic aneurysm.

          Abdominal aortic aneurysms cause 1.3% of all deaths among men aged 65-85 years in developed countries. These aneurysms are typically asymptomatic until the catastrophic event of rupture. Repair of large or symptomatic aneurysms by open surgery or endovascular repair is recommended, whereas repair of small abdominal aortic aneurysms does not provide a significant benefit. Abdominal aortic aneurysm is linked to the degradation of the elastic media of the atheromatous aorta. An inflammatory cell infiltrate, neovascularisation, and production and activation of various proteases and cytokines contribute to the development of this disorder, although the underlying mechanisms are unknown. In this Seminar, we aim to provide an updated review of the pathophysiology, current and new diagnostic procedures, assessment, and treatment of abdominal aortic aneurysm to provide family practitioners with a working knowledge of this disorder.
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            Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production.

            The gene Ucp2 is a member of a family of genes found in animals and plants, encoding a protein homologous to the brown fat uncoupling protein Ucp1 (refs 1-3). As Ucp2 is widely expressed in mammalian tissues, uncouples respiration and resides within a region of genetic linkage to obesity, a role in energy dissipation has been proposed. We demonstrate here, however, that mice lacking Ucp2 following targeted gene disruption are not obese and have a normal response to cold exposure or high-fat diet. Expression of Ucp2 is robust in spleen, lung and isolated macrophages, suggesting a role for Ucp2 in immunity or inflammatory responsiveness. We investigated the response to infection with Toxoplasma gondii in Ucp2-/- mice, and found that they are completely resistant to infection, in contrast with the lethality observed in wild-type littermates. Parasitic cysts and inflammation sites in brain were significantly reduced in Ucp2-/- mice (63% decrease, P<0.04). Macrophages from Ucp2-/- mice generated more reactive oxygen species than wild-type mice (80% increase, P<0.001) in response to T. gondii, and had a fivefold greater toxoplasmacidal activity in vitro compared with wild-type mice (P<0.001 ), which was absent in the presence of a quencher of reactive oxygen species (ROS). Our results indicate a role for Ucp2 in the limitation of ROS and macrophage-mediated immunity.
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              Oxidative stress in vascular disease: causes, defense mechanisms and potential therapies.

              Endothelial cells control vascular homeostasis by generating paracrine factors that regulate vascular tone, inhibit platelet function, prevent adhesion of leukocytes, and limit proliferation of vascular smooth muscle. The dominant factor responsible for many of those effects is endothelium-derived nitric oxide (NO). Endothelial dysfunction characterized by enhanced inactivation or reduced synthesis of NO, alone or in combination, is seen in conjunction with risk factors for cardiovascular disease. Endothelial dysfunction can promote vasospasm, thrombosis, vascular inflammation, and proliferation of the intima. Vascular oxidative stress and increased production of reactive oxygen species contributes to mechanisms of vascular dysfunction. Oxidative stress is mainly caused by an imbalance between the activity of endogenous pro-oxidative enzymes (such as NADPH oxidase, xanthine oxidase or the mitochondrial respiratory chain) and antioxidant enzymes (such as superoxide dismutase, glutathione peroxidase, heme oxygenase, thioredoxin peroxidase/peroxiredoxin, catalase and paraoxonase). In addition, small-molecular-weight antioxidants might have a role in the defense against oxidative stress. Increased concentrations of reactive oxygen species reduce bioactive NO through chemical inactivation, forming toxic peroxynitrite, which in turn can uncouple endothelial NO synthase to form a dysfunctional superoxide-generating enzyme that contributes further to oxidative stress. The role of oxidative stress in vascular dysfunction and atherogenesis, and strategies for its prevention are discussed.
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                Author and article information

                Contributors
                Role: Data curationRole: InvestigationRole: Methodology
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: Funding acquisition
                Role: Funding acquisition
                Role: Project administrationRole: Resources
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                6 July 2017
                2017
                : 12
                : 7
                : e0179743
                Affiliations
                [001]Department of Cardiology, Chengdu Military General Hospital, Chengdu, Sichuan, P.R. China
                Maastricht University, NETHERLANDS
                Author notes

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

                ‡ These authors are co-first authors on this work.

                Author information
                http://orcid.org/0000-0002-0077-6568
                Article
                PONE-D-17-01922
                10.1371/journal.pone.0179743
                5500278
                28683125
                b0d1ce7f-b06e-49d2-85f3-7ae31c7e86da
                © 2017 Yan 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
                : 15 January 2017
                : 2 June 2017
                Page count
                Figures: 5, Tables: 0, Pages: 13
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81500224
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81670419
                Award Recipient :
                Funded by: China Postdoctoral Science Foundation funded project
                Award ID: 2016M593044
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81470396
                Award Recipient :
                These studies were supported in part by grants from National Natural Science Foundation of China (no. 81500224; 81670419; 81470396), China Postdoctoral Science Foundation funded project (no. 2016M593044). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Death
                Apoptosis
                Biology and Life Sciences
                Anatomy
                Cardiovascular Anatomy
                Blood Vessels
                Aorta
                Medicine and Health Sciences
                Anatomy
                Cardiovascular Anatomy
                Blood Vessels
                Aorta
                Medicine and Health Sciences
                Vascular Medicine
                Vascular Diseases
                Aneurysms
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Gene Expression and Vector Techniques
                Protein Expression
                Research and Analysis Methods
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Gene Expression and Vector Techniques
                Protein Expression
                Biology and Life Sciences
                Biochemistry
                Antioxidants
                Biology and Life Sciences
                Biochemistry
                Bioenergetics
                Energy-Producing Organelles
                Mitochondria
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Energy-Producing Organelles
                Mitochondria
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Molecular Probe Techniques
                Immunoblotting
                Research and Analysis Methods
                Molecular Biology Techniques
                Molecular Probe Techniques
                Immunoblotting
                Research and Analysis Methods
                Specimen Preparation and Treatment
                Staining
                Group-Specific Staining
                Hematoxylin Staining
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