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      Oxidative Stress: A Unifying Paradigm in Hypertension

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          Abstract

          The etiology of hypertension involves complex interactions among genetic, environmental, and pathophysiologic factors that influence many regulatory systems. Hypertension is characteristically associated with vascular dysfunction, cardiovascular remodelling, renal dysfunction, and stimulation of the sympathetic nervous system. Emerging evidence indicates that the immune system is also important and that activated immune cells migrate and accumulate in tissues promoting inflammation, fibrosis, and target-organ damage. Common to these processes is oxidative stress, defined as an imbalance between oxidants and antioxidants in favour of the oxidants that leads to a disruption of oxidation-reduction (redox) signalling and control and molecular damage. Physiologically, reactive oxygen species (ROS) act as signalling molecules and influence cell function through highly regulated redox-sensitive signal transduction. In hypertension, oxidative stress promotes posttranslational modification (oxidation and phosphorylation) of proteins and aberrant signalling with consequent cell and tissue damage. Many enzymatic systems generate ROS, but NADPH oxidases (Nox) are the major sources in cells of the heart, vessels, kidneys, and immune system. Expression and activity of Nox are increased in hypertension and are the major systems responsible for oxidative stress in cardiovascular disease. Here we provide a unifying concept where oxidative stress is a common mediator underlying pathophysiologic processes in hypertension. We focus on some novel concepts whereby ROS influence vascular function, aldosterone/mineralocorticoid actions, and immunoinflammation, all important processes contributing to the development of hypertension.

          Résumé

          L'étiologie de l'hypertension implique des interactions complexes entre les facteurs génétiques, environnementaux et physiopathologiques qui influencent de nombreux systèmes de régulation. L'hypertension est typiquement associée à une dysfonction vasculaire, à un remodelage cardiovasculaire, à une dysfonction rénale et à une stimulation du système nerveux sympathique. De nouvelles données indiquent que le système immunitaire est également important et que les cellules immunitaires activées migrent et s'accumulent dans les tissus, favorisant l'inflammation, la fibrose et la lésion des organes cibles. Ces processus ont en commun le stress oxydatif, défini comme étant un déséquilibre entre les oxydants et les antioxydants en faveur des oxydants qui conduit à une perturbation de la signalisation et du contrôle de l'oxydoréduction (redox) et à des dommages moléculaires. Physiologiquement, les espèces réactives de l'oxygène (ERO) agissent comme des molécules de signalisation et influencent la fonction cellulaire par une transduction du signal hautement régulée et sensible à l'oxydoréduction. Dans l'hypertension, le stress oxydatif favorise la modification post-traductionnelle (oxydation et phosphorylation) des protéines et une signalisation aberrante avec des dommages conséquents aux cellules et aux tissus. De nombreux systèmes enzymatiques génèrent des ERO, mais les NADPH oxydases (Nox) en sont les principales sources dans les cellules du cœur, des vaisseaux, des reins et du système immunitaire. L'expression et l'activité des Nox sont accrues en cas d'hypertension et sont les principaux systèmes responsables du stress oxydatif dans les maladies cardiovasculaires. Nous présentons ici un concept unificateur dans lequel le stress oxydatif est un médiateur commun qui sous-tend les processus physiopathologiques de l'hypertension. Nous nous concentrons sur quelques nouveaux concepts selon lesquels les ERO influencent la fonction vasculaire, les actions de l'aldostérone et des minéralocorticoïdes, et l'immuno-inflammation, autant de processus importants contribuant au développement de l'hypertension.

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          Most cited references126

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          Diabetes, Hypertension, and Cardiovascular Disease: Clinical Insights and Vascular Mechanisms

          Hypertension and type 2 diabetes are common comorbidities. Hypertension is twice as frequent in patients with diabetes compared with those who do not have diabetes. Moreover, patients with hypertension often exhibit insulin resistance and are at greater risk of diabetes developing than are normotensive individuals. The major cause of morbidity and mortality in diabetes is cardiovascular disease, which is exacerbated by hypertension. Accordingly, diabetes and hypertension are closely interlinked because of similar risk factors, such as endothelial dysfunction, vascular inflammation, arterial remodelling, atherosclerosis, dyslipidemia, and obesity. There is also substantial overlap in the cardiovascular complications of diabetes and hypertension related primarily to microvascular and macrovascular disease. Common mechanisms, such as upregulation of the renin-angiotensin-aldosterone system, oxidative stress, inflammation, and activation of the immune system likely contribute to the close relationship between diabetes and hypertension. In this article we discuss diabetes and hypertension as comorbidities and discuss the pathophysiological features of vascular complications associated with these conditions. We also highlight some vascular mechanisms that predispose to both conditions, focusing on advanced glycation end products, oxidative stress, inflammation, the immune system, and microRNAs. Finally, we provide some insights into current therapies targeting diabetes and cardiovascular complications and introduce some new agents that may have vasoprotective therapeutic potential in diabetes.
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            Hypertension

            Systemic arterial hypertension is the most important modifiable risk factor for all-cause morbidity and mortality worldwide and is associated with an increased risk of cardiovascular disease (CVD). Fewer than half of those with hypertension are aware of their condition, and many others are aware but not treated or inadequately treated, although successful treatment of hypertension reduces the global burden of disease and mortality. The aetiology of hypertension involves the complex interplay of environmental and pathophysiological factors that affect multiple systems, as well as genetic predisposition. The evaluation of patients with hypertension includes accurate standardized blood pressure (BP) measurement, assessment of the patients' predicted risk of atherosclerotic CVD and evidence of target-organ damage, and detection of secondary causes of hypertension and presence of comorbidities (such as CVD and kidney disease). Lifestyle changes, including dietary modifications and increased physical activity, are effective in lowering BP and preventing hypertension and its CVD sequelae. Pharmacological therapy is very effective in lowering BP and in preventing CVD outcomes in most patients; first-line antihypertensive medications include angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, dihydropyridine calcium-channel blockers and thiazide diuretics.
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              Oxygen radicals, nitric oxide, and peroxynitrite: Redox pathways in molecular medicine

              Aerobic life in humans imposes the hazard of excess oxidation in cell and tissue components that may compromise cell function and viability. The formation and accumulation of oxidized products in biomolecules such as proteins and lipids are observed in various pathologies and during the normal aging process. This review article aims to integrate some early and remarkable discoveries in the field, with more recent developments that helped to define a causative role of oxygen radicals, nitric oxide, and peroxynitrite in human physiology and pathology. These aspects of human redox biochemistry contribute to the understanding of the molecular basis of diseases and aging and open avenues for the development of preventive and therapeutic strategies in molecular medicine. Oxygen-derived free radicals and related oxidants are ubiquitous and short-lived intermediates formed in aerobic organisms throughout life. These reactive species participate in redox reactions leading to oxidative modifications in biomolecules, among which proteins and lipids are preferential targets. Despite a broad array of enzymatic and nonenzymatic antioxidant systems in mammalian cells and microbes, excess oxidant formation causes accumulation of new products that may compromise cell function and structure leading to cell degeneration and death. Oxidative events are associated with pathological conditions and the process of normal aging. Notably, physiological levels of oxidants also modulate cellular functions via homeostatic redox-sensitive cell signaling cascades. On the other hand, nitric oxide ( • NO), a free radical and weak oxidant, represents a master physiological regulator via reversible interactions with heme proteins. The bioavailability and actions of • NO are modulated by its fast reaction with superoxide radical ( O 2 • − ), which yields an unusual and reactive peroxide, peroxynitrite, representing the merging of the oxygen radicals and • NO pathways. In this Inaugural Article, I summarize early and remarkable developments in free radical biochemistry and the later evolution of the field toward molecular medicine; this transition includes our contributions disclosing the relationship of • NO with redox intermediates and metabolism. The biochemical characterization, identification, and quantitation of peroxynitrite and its role in disease processes have concentrated much of our attention. Being a mediator of protein oxidation and nitration, lipid peroxidation, mitochondrial dysfunction, and cell death, peroxynitrite represents both a pathophysiologically relevant endogenous cytotoxin and a cytotoxic effector against invading pathogens.
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                Author and article information

                Contributors
                Journal
                Can J Cardiol
                Can J Cardiol
                The Canadian Journal of Cardiology
                Pulsus Group
                0828-282X
                1916-7075
                1 May 2020
                May 2020
                : 36
                : 5
                : 659-670
                Affiliations
                [1]Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland, United Kingdom
                Author notes
                []Corresponding author: Dr Rhian M. Touyz, Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, United Kingdom. Tel.: +44 (0) 141-330-7775/7774; fax: +44 (0) 141-330-3360. rhian.touyz@ 123456glasgow.ac.uk
                Article
                S0828-282X(20)30186-0
                10.1016/j.cjca.2020.02.081
                7225748
                32389339
                fa4e8ca7-443d-4168-aa37-9149fa64eff8
                © 2020 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 10 January 2020
                : 19 February 2020
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