Does superoxide underlie the pathogenesis of hypertension?

Abstract

Although active oxygen species play important roles in the pathogenesis of various diseases, the molecular mechanism for oxygen toxicity in vascular diseases remains to be elucidated. Since endothelium-derived relaxing factor (EDRF) is inactivated by superoxide radicals in vitro, oxidative stress in and around vascular endothelial cells may affect the circulatory status of animals. To study the role of superoxide radicals and related enzymes, such as superoxide dismutase (SOD), in vascular diseases, we have developed a fusion protein (HB-SOD) consisting of human Cu/Zn-type SOD and a C-terminal basic peptide with high affinity for heparan sulfate on endothelial cells. When injected intravenously, BB-SOD bound to vascular endothelial cells, underwent transcellular transport, and localized within vascular walls by a heparininhibitable mechanism. The blood pressure of spontaneously hypertensive rats (SHR) but not normal animals was decreased significantly by HB-SOD. Heparin inhibited the depressor effect of HB-SOD. In contrast, native SOD had no effect on blood pressure of either SHR or normal rats. Neither H202-inactivated HB-SOD nor the C-terminal heparin-binding peptide showed such a depressor effect, suggesting that the catalytic function of HB-SOD is responsible for its depressor action. To know the source of superoxide radicals, we determined xanthine oxidase activity in the aorta and uric acid levels in the plasma. Although no appreciable difference in xanthine oxidase activity was found between the two animal groups, uric acid levels were significantly higher in SHR than in normal rats. Oxypurinol, a potent inhibitor of xanthine oxidase, also decreased the blood pressure of SHR but not of normal rats. These rmdings indicate that superoxide radicals in and around vascular endothelial cells play critical roles in the pathogenesis of hypertension of SHR.Reactive oxygen species play critical roles in the pathogenesis of various diseases, such as cardiovascular injury associated with circulatory disturbance (1, 2). Many factors, such as endothelin and endothelium-derived relaxing factor (EDRF), affect the circulatory status of animals by modulating vascular resistance. Nitric oxide (NO) and NOgenerated compounds account for the biological actions of EDRF (3, 4). EDRF is synthesized predominantly in vascular endothelial cells and is transferred to smooth muscle cells, where it facilitates cGMP generation leading to vasodilatation. Superoxide radicals can inactivate NO and, hence, EDRF-dependent relaxation of aortic rings and endotheliumdenuded aortas was enhanced by Cu/Zn-type superoxide dismutpse (SOD) (5, 6). Based on such in vitro experiments, superoxide radicals have been postulated to affect vascular resistai e by inactivating EDRF. Since intravenously injected eu/Zn-SOD lacks tissue-specific localization and disappears rapidly from the circulation, predom'iantly due to The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marjceq "ad...

Impact of the components of metabolic syndrome on oxidative stress and enzymatic antioxidant activity in essential hypertension

“…25 Moreover, reducing superoxide radicals by infusion of SOD significantly decreases BP in spontaneously hypertensive rats. 26 In humans, hypertension is also considered a state of OX that can be related to the development of artherosclerosis 27 and other hypertension-induced organ damage, 28 microalbuminuria. The increased OX in hypertensives has been attributed to the overactivity of mechanisms that increase ROS production which is mainly mediated by superoxide and hydroxyl radicals.…”

Total antioxidant status and oxidative DNA damage in a South Indian population of essential hypertensives

“…1 Recent experimental evidence suggests that oxidative stress has an important function in the development of high BP in some animal model. 2 It has been proposed that release of oxygen-free radicals would be stimulated by acute hypertension and this increase in oxygen-free radicals might mediate the vascular damage, which can be seen in hypertensive subjects. Oxygen-free radicals are highly reactive and can react with cellular membranes damaging them through lipid peroxidation.…”

Evaluation of the antioxidant response in the plasma of healthy or hypertensive subjects after short-term exercise

“…Several lines of evidence suggest that hypertension is associated with enhanced oxidative stress. 9,[31][32][33] In particular, it has been proposed that superoxide anions might trigger the development of hypertension, by inactivating endothelium-derived nitric oxide, thus impairing its beneficial and protective effects on the vessel wall. 9 In essential hypertension, both the plasma levels of lipid peroxides and the leucocyte production of superoxide anion or hydrogen peroxide were found increased, 32 while the levels of antioxidants, including Toc, were found decreased.…”

“…9,[31][32][33] In particular, it has been proposed that superoxide anions might trigger the development of hypertension, by inactivating endothelium-derived nitric oxide, thus impairing its beneficial and protective effects on the vessel wall. 9 In essential hypertension, both the plasma levels of lipid peroxides and the leucocyte production of superoxide anion or hydrogen peroxide were found increased, 32 while the levels of antioxidants, including Toc, were found decreased. 31,32 A body of information on the improvement of endotheliumdependent vasodilation by antioxidants is available, and confirms that increased ROS production plays a major role in the pathogenesis of hypertension.…”

“…7,8 It has been proposed that endothelial dysfunction associated with hypertension might be caused by augmented production of the superoxide anion, a radical impairing the endothelium ability to induce NOmediated relaxation of underlying smooth muscle cells. [9][10][11][12] The rapid reaction of nitric oxide with superoxide generates a potent oxidising species, the peroxynitrite anion (ONOO À ), a powerful lipid, protein, and DNA oxidant, which can be detected by increased 3-nitrotyrosine (N-Tyr) level in injured tissues. 13,14 N-Tyr residues have been recently identified also in human atherosclerotic plaques.…”