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      The Role of Nrf2 Signaling in PPAR β/ δ-Mediated Vascular Protection against Hyperglycemia-Induced Oxidative Stress

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          Abstract

          Hyperglycemia induces oxidative stress and plays a substantial role in the progression of vascular diseases. Here, we demonstrated the potentiality of peroxisome proliferator-activated receptor (PPAR) β/ δ activation in attenuating high glucose-induced oxidative stress in endothelial cells and diabetic rats, pointing to the involvement of nuclear factor erythroid 2-related factor 2 (Nrf2). HUVECs exposed to high glucose showed increased levels of reactive oxygen species (ROS) and upregulated NOX-2, NOX-4, Nrf2, and NQO-1 effects that were significantly reversed by the PPAR β/ δ agonists GW0742 and L165041. Both PPAR β/ δ agonists, in a concentration-dependent manner, induced transcriptional and protein upregulation of heme oxygenase-1 (HO-1) under low- and high-glucose conditions. All effects of PPAR β/ δ agonists were reversed by either pharmacological inhibition or siRNA-based downregulation of PPAR β/ δ. These in vitro findings were confirmed in diabetic rats treated with GW0742. In conclusion, PPAR β/ δ activation confers vascular protection against hyperglycemia-induced oxidative stress by suppressing NOX-2 and NOX-4 expression plus a direct induction of HO-1; with the subsequent downregulation of the Nrf2 pathway. Thus, PPAR β/ δ activation could be of interest to prevent the progression of diabetic vascular complications.

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          Most cited references31

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          Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system.

          The NADPH oxidase (Nox) enzymes are critical mediators of cardiovascular physiology and pathophysiology. These proteins are expressed in virtually all cardiovascular cells, and regulate such diverse functions as differentiation, proliferation, apoptosis, senescence, inflammatory responses and oxygen sensing. They target a number of important signaling molecules, including kinases, phosphatases, transcription factors, ion channels, and proteins that regulate the cytoskeleton. Nox enzymes have been implicated in many different cardiovascular pathologies: atherosclerosis, hypertension, cardiac hypertrophy and remodeling, angiogenesis and collateral formation, stroke, and heart failure. In this review, we discuss in detail the biochemistry of Nox enzymes expressed in the cardiovascular system (Nox1, 2, 4, and 5), their roles in cardiovascular cell biology, and their contributions to disease development.
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            Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases.

            Diabetes mellitus is associated to an increased risk of cardiovascular diseases. Hyperglycemia is an important factor in cardiovascular damage, working through different mechanisms such as activation of protein kinase C, polyol and hexosamine pathways, advanced glycation end products production. All of these pathways, in association to hyperglycemia-induced mitochondrial dysfunction and endoplasmic reticulum stress, promote reactive oxygen species (ROS) accumulation that, in turn, promote cellular damage and contribute to the diabetic complications development and progression. ROS can directly damage lipids, proteins or DNA and modulate intracellular signaling pathways, such as mitogen activated protein kinases and redox sensitive transcription factors causing changes in protein expression and, therefore, irreversible oxidative modifications. Hyperglycemia-induced oxidative stress induces endothelial dysfunction that plays a central role in the pathogenesis of micro- and macro-vascular diseases. It may also increase pro-inflammatory and pro-coagulant factors expression, induce apoptosis and impair nitric oxide release. Oxidative stress induces several phenotypic alterations also in vascular smooth-muscle cell (VSMC). ROS is one of the factors that can promote both VSMC proliferation/migration in atherosclerotic lesions and VSMC apoptosis, which is potentially involved in atherosclerotic plaque instability and rupture. Currently, there are contrasting clinical evidences on the benefits of antioxidant therapies in the prevention/treatment of diabetic cardiovascular complications. Appropriate glycemic control, in which both hypoglycemic and hyperglycemic episodes are reduced, in association to the treatment of dyslipidemia, hypertension, kidney dysfunction and obesity, conditions which are also associated to ROS overproduction, can counteract oxidative stress and, therefore, both microvascular and macrovascular complications of diabetes mellitus.
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              NADPH oxidases in vascular pathology.

              Reactive oxygen species (ROS) play a critical role in vascular disease. While there are many possible sources of ROS, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases play a central role. They are a source of "kindling radicals," which affect other enzymes, such as nitric oxide synthase endothelial nitric oxide synthase or xanthine oxidase. This is important, as risk factors for atherosclerosis (hypertension, diabetes, hypercholesterolemia, and smoking) regulate the expression and activity of NADPH oxidases in the vessel wall. There are seven isoforms in mammals: Nox1, Nox2, Nox3, Nox4, Nox5, Duox1 and Duox2. Nox1, Nox2, Nox4, and Nox5 are expressed in endothelium, vascular smooth muscle cells, fibroblasts, or perivascular adipocytes. Other homologues have not been found or are expressed at very low levels; their roles have not been established. Nox1/Nox2 promote the development of endothelial dysfunction, hypertension, and inflammation. Nox4 may have a role in protecting the vasculature during stress; however, when its activity is increased, it may be detrimental. Calcium-dependent Nox5 has been implicated in oxidative damage in human atherosclerosis. NADPH oxidase-derived ROS play a role in vascular pathology as well as in the maintenance of normal physiological vascular function. We also discuss recently elucidated mechanisms such as the role of NADPH oxidases in vascular protection, vascular inflammation, pulmonary hypertension, tumor angiogenesis, and central nervous system regulation of vascular function and hypertension. Understanding the role of individual oxidases and interactions between homologues in vascular disease is critical for efficient pharmacological regulation of vascular NADPH oxidases in both the laboratory and clinical practice.
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                Author and article information

                Contributors
                Journal
                Oxid Med Cell Longev
                Oxid Med Cell Longev
                OMCL
                Oxidative Medicine and Cellular Longevity
                Hindawi
                1942-0900
                1942-0994
                2018
                25 June 2018
                : 2018
                : 5852706
                Affiliations
                1Department of Pharmacology, School of Pharmacy, University of Granada, Granada, Spain
                2Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
                3Ciber-Enfermedades Cardiovasculares (CIBERCV), Granada, Spain
                4Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni Suef, Egypt
                5Department of Endocrinology, Diabetes and Nutrition, Charité-University Medicine Berlin, Berlin, Germany
                6Department of Endocrinology, Diabetes and Nutrition at the Center for Cardiovascular Research (CCR), Charité-University Medicine Berlin, Berlin, Germany
                Author notes

                Academic Editor: Simona Bungau

                Author information
                http://orcid.org/0000-0003-3872-2669
                http://orcid.org/0000-0003-2452-9286
                Article
                10.1155/2018/5852706
                6036815
                30046379
                074abfd9-97f0-404a-94ab-aaa7c43ff728
                Copyright © 2018 Rosario Jimenez et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 23 January 2018
                : 18 February 2018
                Funding
                Funded by: Instituto de Salud Carlos III
                Award ID: RD12/0042/0011
                Funded by: Junta de Andalucía
                Award ID: P12-CTS-2722
                Funded by: Fondo Europeo de Desarrollo Regional (FEDER)
                Award ID: SAF2014-55523-R
                Award ID: SAF2011-28150
                Award ID: SAF2010-22066-C02-01
                Funded by: Ministerio de Economía y Competitividad
                Categories
                Research Article

                Molecular medicine
                Molecular medicine

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