Oxidative Stress Produced by Angiotensin Too
1997; Lippincott Williams & Wilkins; Volume: 95; Issue: 3 Linguagem: Inglês
10.1161/01.cir.95.3.557
ISSN1524-4539
AutoresHelgi Oskarsson, Donald D. Heistad,
Tópico(s)Hormonal Regulation and Hypertension
ResumoHomeCirculationVol. 95, No. 3Oxidative Stress Produced by Angiotensin Too Free AccessResearch ArticleDownload EPUBAboutView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticleDownload EPUBOxidative Stress Produced by Angiotensin TooImplications for Hypertension and Vascular Injury Helgi J. Oskarsson and Donald D. Heistad Helgi J. OskarssonHelgi J. Oskarsson the Department of Internal Medicine, Division of Cardiovascular Diseases, University of Iowa Hospitals and Clinics, Iowa City. and Donald D. HeistadDonald D. Heistad the Department of Internal Medicine, Division of Cardiovascular Diseases, University of Iowa Hospitals and Clinics, Iowa City. Originally published4 Feb 1997https://doi.org/10.1161/01.CIR.95.3.557Circulation. 1997;95:557–559Since the landmark study on renovascular hypertension by Goldblatt et al in 1934,1 it has become clear that the RAS plays a major role in hypertension and other cardiovascular disorders. Although the mechanism for RAS-induced hypertension is generally attributed to vasoconstrictor effects of angiotensin II and the salt- and water-retaining effects of aldosterone, a study by Bech Laursen et al in this issue of Circulation2 suggests an additional mechanism.Evidence That Angiotensin II Causes Hypertension via Production of Superoxide RadicalThe study by Bech Laursen et al, coupled with their previous findings,3 suggests that angiotensin II–induced hypertension in rats is associated with a large increase in vascular production of superoxide radical, which is accompanied by impairment of EDNO-dependent vasodilation. This was not observed in rats made equally hypertensive by norepinephrine infusion.The authors also observed that chronic infusion of liposome-encapsulated SOD increased conduit vessel SOD activity by 30%. This rather modest increase in SOD activity was nevertheless associated with normalization of superoxide release in the aorta from rats made hypertensive by angiotensin II, with restoration of normal EDNO-dependent vasorelaxation.In addition, the authors showed that the development of hypertension in response to long-term infusion of angiotensin II was significantly inhibited by coadministration of liposome-encapsulated SOD, whereas the same treatment had no effect on hypertension induced by infusion of norepinephrine. Furthermore, rats with angiotensin II–induced hypertension that received liposome-encapsulated SOD showed a significantly greater reduction in mean arterial blood pressure in response to the endothelium-dependent vasodilator acetylcholine than did rats that were not treated with SOD. This suggests that SOD supplementation improves endothelial function not only in conduit arteries but also in resistance vessels.Bech Laursen et al conclude that a substantial portion of angiotensin II–mediated hypertension is produced by an increase in endogenous superoxide production by vessels, leading to degradation of EDNO.Importance of the ResultsThe data provided in the present study of Bech Laursen et al are important because they provide evidence for an underappreciated mechanism by which angiotensin II can produce hypertension. Nevertheless, it should be noted that although liposome-encapsulated SOD therapy normalized superoxide production by vessels and was associated with significant reduction in arterial pressure in rats treated with angiotensin II, their blood pressure remained elevated. This persistent elevation of pressure suggests additional mechanisms for angiotensin II–mediated hypertension, which may include direct vasoconstrictor effects of angiotensin II, and angiotensin II–mediated increase in release of endothelin,4 vasoconstrictor prostanoids,5 and lipoxygenase products.6Perhaps of even greater importance is the general implication of oxidative stress induced by angiotensin II, through which the RAS not only influences blood pressure but theoretically may affect a variety of other important biological phenomena that are relevant to vascular pathophysiology.Implications of Angiotensin II–Mediated Oxidative StressBy interfering with the bioavailability of EDNO,7 increased superoxide production potentially has many important consequences related to the numerous effects of EDNO within the vessel wall and lumen. EDNO inhibits platelet adhesion and aggregation, decreases leukocyte adherence to endothelium, produces vasodilation, and inhibits smooth muscle cell proliferation and production of extracellular matrix. Furthermore, the reaction of NO with superoxide radical leads to formation of peroxynitrite, a reactive oxygen species that can initiate lipid peroxidation and may be toxic to cells.8 Peroxynitrite may also play a role in oxidation of lipoproteins within the vessel wall, an important step in the development of atherosclerosis.9In addition, increased production and release of reactive oxygen species within the vessel wall may directly produce vasoconstriction,10 affect platelet activation,11 and influence intracoronary thrombosis.12 Furthermore, angiotensin II enhances the release of plasminogen activator inhibitor,13 perhaps in part by enhanced oxidative stress.14Reactive oxygen species may also represent an important signal transduction pathway inside cells.15 They have been shown to participate in the expression of cell-adhesion molecules on endothelial cells.1617 They also may play a role in the activation of several early-response elements such as c-fos and c-jun, which are known to be stimulated by angiotensin II, in part via reactive oxygen intermediates,18 which can lead to cell proliferation or hypertrophy, depending on interaction with other growth factors.Thus, by increasing production of free radicals within the vessel wall, angiotensin II, at least theoretically, can influence processes that affect vascular tone, vascular remodeling, development of atherosclerosis and neointimal proliferation, and intravascular thrombosis. This mechanism could contribute to the observed association among various genotypes that influence RAS activity and appear to affect the risk of cardiovascular complications such as atherosclerosis, myocardial infarction, and stroke,19202122 regardless of whether the patients are hypertensive. Similarly, this mechanism could provide a rational for the provocative hypothesis that elevation of renin levels in patients with hypertension may be a risk factor for cardiovascular events, a hypothesis that is supported by some23 but not all studies.24Taken together, these observations support the notion that activity of the RAS has important implications beyond its well-recognized role in the pathophysiology of hypertension.Relevance to the Clinical Effects of ACE InhibitorsACE inhibitors block the conversion of angiotensin I to angiotensin II and therefore presumably decrease oxidative stress induced by angiotensin II. This may explain some of the benefits observed in clinical trials with ACE-inhibitor therapy in patients with cardiovascular diseases. For example, ACE inhibitors have been reported to improve endothelium-dependent coronary vasodilatation in patients with atherosclerosis.25 The data presented by Bech Laursen et al2 suggest that if endogenous free radical production in vessels can be inhibited and degradation of NO reduced, EDNO-dependent vasodilation is improved. Therefore, one mechanism by which ACE inhibitors may improve endothelium-dependent vasodilation is by blocking angiotensin II–mediated production of superoxide radical.26 Furthermore, ACE inhibitors inhibit degradation of bradykinin and other kinins. Because bradykinin releases both NO and prostacyclin from endothelial cells, ACE inhibition may both increase release and decrease superoxide-mediated degradation of these important vasodilators and platelet inhibitors. Perhaps the decreased risk for recurrent ischemic cardiac events in patients after myocardial infarction randomized to ACE-inhibitor therapy in the SAVE27 and the SOLVE28 trials can be explained in part by this mechanism.ConclusionsIn summary, the demonstration of angiotensin II–induced free radical generation in vessels as a mechanism for hypertension and as a potential mechanism by which the RAS influences the pathophysiology of various other cardiovascular disorders is an important contribution to vascular biology. Similarly, in light of evidence that oxidative stress plays a major role in development of cardiovascular disorders, inhibition of this mechanism may contribute to the efficacy of clinical interventions targeted toward the RAS in a variety of cardiovascular diseases.Selected Abbreviations and AcronymsEDNO=endothelium-derived nitric oxideNO=nitric oxideRAS=renin-angiotensin systemSOD=superoxide dismutaseThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Helgi J. Oskarsson, MD, Assistant Professor, Department of Internal Medicine, Division of Cardiovascular Diseases, University of Iowa Hospitals and Clinics, 200 Hawkins Dr, Iowa City, IA 52242. E-mail [email protected] References 1 Goldblatt H, Lynch J, Hanzal RF, Summerville WW. Studies on experimental hypertension, I: the production of persistent elevation of systolic blood pressure by means of renal ischemia. 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