Moderate exercise decreases inflammation and oxidative stress in hypertension: but what are the mechanisms?

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.3 Positive 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 B (NFB) system.6 Despite 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 NFB.6 Physiological concentrations of interleukin (IL) 6 stimulate the appearance in the circulation of the antiinflammatory cytokines IL-1 receptor antagonist and IL-10 and inhibit the production of the proinflammatory cytokine tumor necrosis factor.8 In addition, a role for the Toll-like receptor 4 in mediating the anti-inflammatory properties of The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. 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. Correspondence 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] (Hypertension. 2009;54:1206-1208.) © 2009 American Heart Association, Inc.