Reactive Oxygen Species, Vascular Oxidative Stress, and Redox Signaling in Hypertension

Abstract

Abstract-Metabolism of oxygen by cells generates potentially deleterious reactive oxygen species (ROS). Under normalconditions the rate and magnitude of oxidant formation is balanced by the rate of oxidant elimination. However, an imbalance between prooxidants and antioxidants results in oxidative stress, which is the pathogenic outcome of oxidant overproduction that overwhelms the cellular antioxidant capacity. The kidney and vasculature are rich sources of NADPH oxidase-derived ROS, which under pathological conditions play an important role in renal dysfunction and vascular damage. Strong experimental evidence indicates that increased oxidative stress and associated oxidative damage are mediators of renovascular injury in cardiovascular pathologies. Increased production of superoxide anion and hydrogen peroxide, reduced nitric oxide synthesis, and decreased bioavailability of antioxidants have been demonstrated in experimental and human hypertension. These findings have evoked considerable interest because of the possibilities that therapies targeted against free radicals by decreasing ROS generation or by increasing nitric oxide availability and antioxidants may be useful in minimizing vascular injury and renal dysfunction and thereby prevent or regress hypertensive end-organ damage. This article highlights current developments in the field of ROS and hypertension, focusing specifically on the role of oxidative stress in hypertension-associated vascular damage. In addition, recent clinical trials investigating cardiovascular benefits of antioxidants are discussed, and some explanations for the rather disappointing results from these studies are addressed. Finally, important avenues for future research in the field of ROS, oxidative stress, and redox signaling in hypertension are considered. Key Words: free radicals Ⅲ antioxidants Ⅲ resistance Ⅲ arteries Ⅲ hypertension, essential C ompelling experimental evidence indicates that reactive oxygen species (ROS) play an important pathophysiological role in the development of hypertension. This is due, in large part, to ⅐O 2 Ϫ excess (oxidative stress) and decreased NO bioavailability in the vasculature and kidneys and to ROS-mediated cardiovascular remodeling. [1][2][3] In human hypertension, biomarkers of systemic oxidative stress are elevated. 4 Treatment with superoxide dismutase (SOD) mimetics or antioxidants improves vascular and renal function, regresses vascular remodeling, and reduces blood pressure (BP). 5,6 Mouse models deficient in ROS-generating enzymes have lower BP compared with wild-type counterparts, and Angiotensin II (Ang II) infusion fails to induce hypertension in these mice. 7 Furthermore, experimental models with compromised antioxidant capacity develop hypertension. 8 In cultured vascular smooth muscle cells (VSMCs) and isolated arteries from hypertensive rats and humans, ROS production is enhanced, redox-dependent signaling is amplified, and antioxidant bioactivity is reduced. 9 Accordingly, evidence at multiple levels supports a role for ox...

Free Radicals: Properties, Sources, Targets, and Their Implication in Various Diseases

“…Increased ROS generation eliminates NO • by forming ONOO -, thus reducing NO • bioavailability which leads to decreased endothelium-dependent vasodilation resulting in hypertension [170]. A decrease in NO bioavailability and an increase in oxidative stress are present in human hypertension [171]. Oxidation-induced impairment of NO also results in reduced opposition to the vasoconstrictive and hypertensive effects of angiotensin II.…”

Endothelial dysfunction and hypertension in aging

“…59,60,68 Ang II-induced NADPH oxidase activation is one of the major sources of ROS in atherosclerosis. 18,19,67,68 Zalba et al 68 showed that endothelial dysfunction is due to an excess of ROS rather than a decrease in NO production in the aorta of spontaneously hypertensive rats and is associated with both upregulation of p22 phox mRNA expression and increased activity of NADPH oxidase. Upregulation of p22 phox mRNA expression is a key component of Ang II-induced NADPH oxidase activation, and increased expression levels of other components also have an important role in this oxidase under pathological conditions.…”

“…Upregulation of p22 phox mRNA expression is a key component of Ang II-induced NADPH oxidase activation, and increased expression levels of other components also have an important role in this oxidase under pathological conditions. 18 Increased mRNA expression levels of p47 phox , p67 phox , p22 phox and gp91 phox have been found in internal mammary arteries of patients with cardiovascular diseases and diabetes mellitus. Guzik et al 19 reported that impairment of acetylcholine-induced vasodilation, increase in NADPH oxidase activity and NADPH oxidase-induced ROS generation in saphenous veins in patients with cardiovascular diseases are related to each other and are associated with increased risk of atherosclerosis.…”

“…An imbalance of reduced production of nitric oxide (NO) or increased production of reactive oxygen species (ROS), mainly superoxide, may promote endothelial dysfunction. [18][19][20] The key mechanism by which endothelium-dependent vasodilation is impaired is an increase in oxidative stress that inactivates NO. When considering aging-related endothelial dysfunction, the role of endothelial cell senescence in endothelial dysfunction should also be discussed.…”

Byproducts of oxidative protein damage and antioxidant enzyme activities in plasma of patients with different degrees of essential hypertension

“…[1][2][3][4] However, the question of whether hypertension or oxidative stress is the primary event, remains still unanswered.…”