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Moderate Exercise Decreases Inflammation and Oxidative Stress in Hypertension

2009; Lippincott Williams & Wilkins; Volume: 54; Issue: 6 Linguagem: Inglês

10.1161/hypertensionaha.109.136622

1524-4563

Ana M. Briones, Rhian M. Touyz,

Exercise and Physiological Responses

HomeHypertensionVol. 54, No. 6Moderate Exercise Decreases Inflammation and Oxidative Stress in Hypertension Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBModerate Exercise Decreases Inflammation and Oxidative Stress in HypertensionBut What Are the Mechanisms? Ana M. Briones and Rhian M. Touyz Ana M. BrionesAna M. Briones From the Kidney Research Centre (A.M.B., R.M.T.), Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada; Departamento Farmacología y Terapéutica (A.M.B.), Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain. and Rhian M. TouyzRhian M. Touyz From the Kidney Research Centre (A.M.B., R.M.T.), Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada; Departamento Farmacología y Terapéutica (A.M.B.), Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain. Originally published19 Oct 2009https://doi.org/10.1161/HYPERTENSIONAHA.109.136622Hypertension. 2009;54:1206–1208Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: October 19, 2009: Previous Version 1 Extensive epidemiological, clinical, and experimental data indicate that physical exercise slows the progression of vascular disease and reduces cardiovascular morbidity and mortality. Physical inactivity is believed to be an independent risk factor for the development of coronary heart disease, stroke, and peripheral vascular disease. As such, regular exercise is rapidly gaining widespread advocacy as a measure for preventing cardiovascular diseases, diabetes mellitus, cancer, and other chronic illnesses. In fact, major clinical guidelines for the management of hypertension suggest that exercise, together with other lifestyle modifications, should be the first line of antihypertensive management.1,2 In support of this, a comprehensive meta-analysis showed that aerobic endurance training reduces systolic blood pressure by 2 to 7 mm Hg with the greatest reduction in hypertensive participants but with blood pressure–lowering effects as well in prehypertensive patients.3Positive cardiovascular effects of exercise are associated with beneficial changes in cholesterol levels, antioxidant systems, blood pressure, adipogenesis, and inflammation. Myriad factors have been implicated, whereby exercise induces protective cardiovascular actions, including decreased sympathetic activity, reduced angiotensin II levels, increased NO bioavailability, increased antioxidant capacity, modulation of K+ channels, and expression of cardioprotective factors, such as apelin.4 In addition, growing evidence indicates that exercise prevents oxidative damage by reducing oxidative stress, an important factor in inflammation and hypertension.5 What remains unclear is exactly how exercise modulates redox status and how it influences proinflammatory processes.In the present issue of Hypertension, Agarwal et al6 further highlight the benefits of exercise in reducing blood pressure and focus on the role of ameliorating oxidative stress and inflammation as putative mechanisms for beneficial effects of exercise. By using the spontaneously hypertensive rat (SHR) model and a moderate training program, they demonstrate that exercise delays the progression of hypertension, a response associated with decreased plasma levels of proinflammatory cytokines and norepinephrine, reduced oxidative stress, and diminished activation of the nuclear factor κB (NF-κB) system.6Despite the many studies demonstrating that exercise reduces oxidative stress, which probably impacts on cardiovascular status, there is a paradox relating to interactions between exercise and the generation of reactive oxygen species. For example, exercise protects against atherosclerosis but also induces oxidative stress as a result of the inefficiency of the mitochondrial respiratory chain and the increase in fluid shear stress on the endothelium.4 Human and experimental studies showed that repeated exposure to mild oxidant stress that occurs with exercise may initiate adaptive processes to reduce oxidative stress by decreasing superoxide anion (O2·−) production and/or upregulating antioxidant enzymes.4 This, together with the exercise-induced increase in shear stress, might contribute to increased NO availability and improvement of vasodilator responses observed during exercise.Some studies have queried how exercise impacts on the source of O2·−, focusing especially on the expression and/or activity of NADPH oxidase, a major enzymatic contributor of O2·− in the cardiovascular system. However, these studies were conducted primarily in normotensive exercising models, with little information available in hypertension. In fact, it is unclear whether exercise actually influences NADPH oxidase activity and NADPH oxidase subunits expression in hypertension. A recent study in humans indicated that exercise had significant effects on oxidative stress and blood pressure in hypertensive patients independent of polymorphisms in p22phox.7 In the study of Agarwal et al,6 exercise training clearly normalized the increased expression of gp91phox and the increased production of reactive oxygen species in the heart of SHRs, as well as induced upregulation of antioxidant enzymes, promoting a low redox milieu.In keeping with other studies, Agarwal et al6 demonstrated that exercise reduces inflammation. As suggested in the article, mechanisms for this may relate to decreased oxidative stress, changes in IL-6 production and decreased activation of NF-κB.6 Physiological concentrations of interleukin (IL) 6 stimulate the appearance in the circulation of the anti-inflammatory cytokines IL-1 receptor antagonist and IL-10 and inhibit the production of the proinflammatory cytokine tumor necrosis factor-α.8 In addition, a role for the Toll-like receptor 4 in mediating the anti-inflammatory properties of exercise has been suggested. This is based on the fact that Toll-like receptor 4 expression is decreased in physically active versus sedentary older women.9 It is also possible that the decrease in reactive oxygen species generation reduces NF-κB activation and consequent cytokine production (Figure). To what extent these phenomena participate in exercise-induced reduction of inflammation in the context of hypertension remains unclear, and unfortunately the study by Agarwal et al6 leaves many unanswered questions as to exactly how exercise actually influences cardiovascular function. Download figureDownload PowerPointFigure. Scheme demonstrating possible mechanisms whereby moderate exercise improves cardiac function and reduces blood pressure (BP) in the SHR. In cardiomyocytes, NE binds to adrenergic receptors and induces activation of NADPH oxidase and superoxide anion (O2·−) production and/or production of proinflammatory cytokines, such as tumor necrosis factor (TNF)-α and IL-1β. In addition, proinflammatory cytokines can activate NADPH oxidase in a circuitous relationship and positive feedforward relationship. O2·− induces NF-κB activation and consequent cytokine production. Moreover, O2·− reacts with inducible NO synthase (iNOS)-derived NO, inducing ONOO− production and tissue damage. These events stimulate redox-sensitive pathways to promote left ventricular hypertrophy (LVH), diastolic dysfunction, and hypertension. Moderate exercise, by inducing decreases in NE levels, might lead to diminished levels of proinflammatory cytokines and/or reactive oxygen species that, in turn, will decrease NF-κB activation and inflammation/oxidative stress. These mechanisms might explain the improved cardiac function and the decrease in blood pressure. + indicates stimulatory effect; −, inhibitory effect; ↑, increase; ↓, decrease.A limitation of the study under discussion is the fact that the data are essentially associative. It is not possible to conclude anything definitive about mechanisms whereby exercise influence molecular/cellular events and signaling pathways. Moreover, the changes observed in oxidative stress and inflammatory biomarkers in the study6 may be interdependent, because there is a circuitous relationship and positive feedforward relationship between free radicals and inflammation/NF-κB (Figure).5 In fact, these data pose the question of whether exercise-induced reduction in oxidative stress is responsible for the anti-inflammatory properties of exercise and/or whether the reduction of cytokines explains the antioxidant properties of exercise. The authors attempt to unravel this issue, in part, by exploring the relationship between the sympathetic nervous and oxidative stress/inflammation system in exercising SHRs.Plasma norepinephrine levels with associated increased sympathetic activation in SHRs may lead to cardiomyocyte hypertrophy, cardiac damage, and apoptosis. It is generally accepted that, in both humans and experimental models, exercise training reduces sympathetic activity and/or increases parasympathetic tone, which are correlated with reduced heart rate and blood pressure. It is also known that increased sympathetic activity is strongly related to cardiac oxidative stress through the formation of reactive oxygen species by catecholamine oxidation but also by stimulating its generation through activation of NADPH oxidase. Interestingly, this catecholamine induced-ROS production participates in cardiomyocyte hypertrophy.10 In addition, norepinephrine induces proinflammatory cytokines in the cardiomyocytes.11 To what extent these reduced norepinephrine levels participate in the decrease in proinflammatory cytokines and reactive oxygen species reported by Agarwal et al6 is not addressed but probably does play a role, because exercise is a powerful modulator of sympathetic activity, which, in turn, influences NADPH oxidase–derived generation of O2·−.A particularly important and clinically relevant question posed by Agarwal et al6 is "How much exercise is actually needed to confer cardiovascular benefits?" These investigators clearly demonstrate that even moderate exercise training is enough to activate molecular pathways leading to decreased inflammation and oxidative stress in SHRs and to attenuate the development of hypertension. In fact, low-to-moderate–intensity exercise appears to be as beneficial as higher-intensity exercise for reducing blood pressure.4 Interestingly, the authors did not find beneficial effects of this training program in normotensive animals, suggesting differential responsiveness between Wistar-Kyoto rats and SHRs. Such data provoke the question as to whether there are different levels of exercise benefits in pathological and physiological conditions. This is an important issue, because Schultz et al12 reported the provocative findings that excessive exercise, in the untreated hypertensive state, can have deleterious effects on cardiac remodeling and may actually accelerate progression to heart failure.The study by Agarwal et al6 has clinical significance because it highlights the fact that even moderate exercise improves cardiac function and attenuates the development of hypertension, possibly by decreasing oxidative stress and inflammation through modulation of the sympathetic nervous system. Although these findings are interesting and support clinical studies, they are still essentially associative. Until we have a greater understanding of exactly how exercise influences the fundamental process at the gene, molecular, and cellular levels, we cannot make any conclusions regarding antihypertensive mechanisms of exercise. Much research is still needed to address these important clinically relevant aspects.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Sources of FundingQuoted studies were funded by grant 44018 from the Canadian Institutes of Health Research. A.M.B. is supported through a Beca de Posgrado from Fundación Caja Madrid. R.M.T. is supported through a Canada Research Chair/Canadian Foundation for Innovation award.DisclosuresNone.FootnotesCorrespondence to Ana M. Briones, Kidney Research Centre, Ottawa Health Research Institute/University of Ottawa, 451 Smyth Rd, Ottawa, Ontario K1H 8M5, Canada. E-mail [email protected] or [email protected] References 1 Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; for the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003; 42: 1206–1252.LinkGoogle Scholar2 Campbell NR, Khan NA, Hill MD, Tremblay G, Lebel M, Kaczorowski J, McAlister FA, Lewanczuk RZ, Tobe S; for the Canadian Hypertension Education Program. 2009 Canadian Hypertension Education Program recommendations: the scientific summary–an annual update. Can J Cardiol. 2009; 25: 271–277.CrossrefMedlineGoogle Scholar3 Cornelissen VA, Fagard RH. Effects of endurance training on blood pressure, blood pressure-regulating mechanisms, and cardiovascular risk factors. Hypertension. 2005; 46: 667–675.LinkGoogle Scholar4 Yung LM, Laher I, Yao X, Chen ZY, Huang Y, Leung FP. Exercise, vascular wall and cardiovascular diseases: an update (part 2). Sports Med. 2009; 39: 45–63.CrossrefMedlineGoogle Scholar5 Schiffrin EL, Touyz RM. From bedside to bench to bedside: role of renin-angiotensin-aldosterone system in remodeling of resistance arteries in hypertension. Am J Physiol Heart Circ Physiol. 2004; 287: H435–H446.CrossrefMedlineGoogle Scholar6 Agarwal D, Haque M, Sriramula S, Mariappan N, Pariaut R, Francis J. Role of proinflammatory cytokines and redox homeostasis in exercise-induced delayed progression of hypertension in spontaneously hypertensive rats. Hypertension. 2009; 54: 1393–1400.LinkGoogle Scholar7 Feairheller DL, Brown MD, Park JY, Brinkley TE, Basu S, Hagberg JM, Ferrell RE, Fenty-Stewart NM. Exercise training, NADPH oxidase p22phox gene polymorphisms, and hypertension. Med Sci Sports Exerc. 2009; 41: 1421–1428.CrossrefMedlineGoogle Scholar8 Petersen AM, Pedersen BK. The anti-inflammatory effect of exercise. J Appl Physiol. 2005; 98: 1154–1162.CrossrefMedlineGoogle Scholar9 Flynn MG, McFarlin BK. Toll-like receptor 4: link to the anti-inflammatory effects of exercise? Exerc Sport Sci Rev. 2006; 34: 176–181.CrossrefMedlineGoogle Scholar10 Amin JK, Xiao L, Pimental DR, Pagano PJ, Singh K, Sawyer DB, Colucci WS. Reactive oxygen species mediate alpha-adrenergic receptor-stimulated hypertrophy in adult rat ventricular myocytes. J Mol Cell Cardiol. 2001; 33: 131–139.CrossrefMedlineGoogle Scholar11 Fu YC, Chi CS, Yin SC, Hwang B, Chiu YT, Hsu SL. Norepinephrine induces apoptosis in neonatal rat cardiomyocytes through a reactive oxygen species-TNF alpha-caspase signaling pathway. Cardiovasc Res. 2004; 62: 558–567.CrossrefMedlineGoogle Scholar12 Schultz RL, Swallow JG, Waters RP, Kuzman JA, Redetzke RA, Said S, de Escobar GM, Gerdes AM. Effects of excessive long-term exercise on cardiac function and myocyte remodeling in hypertensive heart failure rats. Hypertension. 2007; 50: 410–416.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Teixeira M, Gouveia M, Duarte A, Ferreira M, Simões M, Conceição M, Silva G, Magalhães S, Ferreira R, Nunes A, Vieira S and Ribeiro F (2019) Regular Exercise Participation Contributes to Better Proteostasis, Inflammatory Profile, and Vasoactive Profile in Patients With Hypertension, American Journal of Hypertension, 10.1093/ajh/hpz160, 33:2, (119-123), Online publication date: 22-Feb-2020. Fan B, Jabeen R, Bo B, Guo C, Han M, Zhang H, Cen J, Ji X and Wei J (2020) What and How Can Physical Activity Prevention Function on Parkinson's Disease?, Oxidative Medicine and Cellular Longevity, 10.1155/2020/4293071, 2020, (1-12), Online publication date: 14-Feb-2020. Al-Jarrah M and Erekat N Treadmill exercise training could attenuate the upregulation of Interleukin-1 beta and tumor necrosis factor alpha in the skeletal muscle of mouse model of chronic/progressive Parkinson disease, NeuroRehabilitation, 10.3233/NRE-182492, 43:4, (501-507) Vas P, Pafili K and Papanas N (2018) Exercise to improve diabetic peripheral neuropathy: An additional option?, Neurophysiologie Clinique, 10.1016/j.neucli.2018.05.001, 48:4, (191-193), Online publication date: 1-Sep-2018. Herrera N, Jesus I, Dionísio E, Dionísio T, Santos C and Amaral S (2017) Exercise Training Prevents Dexamethasone-induced Rarefaction, Journal of Cardiovascular Pharmacology, 10.1097/FJC.0000000000000505, 70:3, (194-201), Online publication date: 1-Sep-2017. Yu A and Jones L (2015) Modulation of cardiovascular toxicity in Hodgkin lymphoma: potential role and mechanisms of aerobic training, Future Cardiology, 10.2217/fca.15.29, 11:4, (441-452), Online publication date: 1-Jul-2015. Vargas W, Dipp T, Plentz R and Rigatto K (2013) Higher Mean Blood Pressure is Associated With Autonomic Imbalance But Not With Endothelial Dysfunction in Young Soccer Players, American Journal of Hypertension, 10.1093/ajh/hps034, 27:4, (508-513), Online publication date: 1-Apr-2014. Mahmoody S, Gharakhanlou R, Roshan V and Hedayati M (2012) Individual and Concomitant Effects of Cardioprotective Programs on Cardiac Apelinergic System and Oxidative State in └-NAME-Induced Hypertension, Clinical and Experimental Hypertension, 10.3109/10641963.2012.685536, 35:1, (20-27), Online publication date: 1-Feb-2013. Doss M (2012) Shifting the Paradigm in Radiation Safety, Dose-Response, 10.2203/dose-response.11-056.Doss, 10:4, (dose-response.1), Online publication date: 1-Oct-2012. Briones A, Arribas S and Salaices M (2010) Role of extracellular matrix in vascular remodeling of hypertension, Current Opinion in Nephrology and Hypertension, 10.1097/MNH.0b013e328335eec9, 19:2, (187-194), Online publication date: 1-Mar-2010. Silva S, Jara Z, Peres R, Lima L, Scavone C, Montezano A, Touyz R, Casarini D, Michelini L and Jourd'heuil D (2017) Temporal changes in cardiac oxidative stress, inflammation and remodeling induced by exercise in hypertension: Role for local angiotensin II reduction, PLOS ONE, 10.1371/journal.pone.0189535, 12:12, (e0189535) December 2009Vol 54, Issue 6 Advertisement Article InformationMetrics https://doi.org/10.1161/HYPERTENSIONAHA.109.136622PMID: 19841287 Originally publishedOctober 19, 2009 PDF download Advertisement SubjectsAnimal Models of Human DiseaseHypertensionOxidant StressRehabilitation