doi: 10.1161/hc0302.102618
(Circulation. 2002;105:393.)
© 2002 American Heart Association, Inc.
Current Perspectives |
The AT1-Type Angiotensin Receptor in Oxidative Stress and Atherogenesis
Part I: Oxidative Stress and Atherogenesis
From Klinik und Poliklinik Innere Medizin III (G.N.), Universität des Saarlandes, Homburg/Saar, Germany; and the Department of Medicine (D.G.H.), Division of Cardiology, Medical School of Emory University, Atlanta, Ga.
Correspondence to Dr Georg Nickenig, Klinik und Poliklinik Innere Medizin III, Universität des Saarlandes, 66421 Homburg/Saar, Germany. E-mail nickenig{at}med-in.uni-sb.de
Key Words: angiotensin • oxygen • atherosclerosis • endothelium • growth substances
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Introduction |
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 Top Introduction AT1 Receptor and Oxidative...References |
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Angiotensin II, the principal effector of the renin angiotensin system, is a multifunctional peptide that modulates blood pressure, water and sodium homeostasis, neuronal function, and other neurohumoral systems.1–3 Initial research with angiotensin II focused on its role in the pathogenesis of hypertension; however, in the past decade, increasing evidence has accumulated to indicate that this octapeptide is involved in the development of atherosclerosis, myocardial infarction, vascular and myocardial remodeling, and congestive heart failure.4–7 The effects of angiotensin II are mediated by 2 plasma membrane receptors, referred to as the AT1 and AT2 subtypes.3,4 In adult tissues, the AT2 receptor is predominantly expressed in the brain and adrenals, with lower levels expressed elsewhere.8 AT2 receptor stimulation leads to vasodilatation and inhibition of vascular smooth muscle growth. During embryogenesis, the AT2 receptor is expressed in developing arteries, and seems to play a role in curbing vascular smooth muscle growth and guiding the ultimate thickness of the vascular wall.8,9 Although interesting and important roles of the AT2 receptor continue to be defined, most of the known functions of angiotensin II are related to AT1 receptor activation. AT1 receptors belong to the 7-membrane–domain superfamily of G-protein–coupled receptors and are expressed in vascular smooth muscle cells, heart, lung, brain, liver, kidney, and adrenal glands.3 AT1 receptors are coupled to a variety of intracellular signaling molecules, including the phospholipases A2, C, and D, adenylate cyclase, voltage-dependent Ca2+ channels, and to a variety of kinases involved in phosphorylation cascades.2–4 Depending on the cell and organ type, stimulation of these signal transduction pathways leads to cellular contraction, hypertrophy, proliferation, and/or apoptosis.2–4,10,11 During the past few years, it has become apparent that one of the most important consequences of AT1 receptor activation, particularly in the cardiovascular system, is the production and release of reactive oxygen species.12,13
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AT1 Receptor and Oxidative Stress |
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TopIntroductionAT1 Receptor and Oxidative...References |
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During normal cellular metabolism, several enzyme systems reduce molecular oxygen, resulting in formation of a variety of reactive oxygen species, including superoxide (O2·-), hydroxyl radical (HO·), hypochlorous acid (HOCl), lipid radicals, and hydrogen peroxide (H2O2).14,15 Reactive oxygen species likely play a critical role in the normal functioning of cells. For example, the normal growth of vascular smooth muscle cells seems to require reactive oxygen species.16 An excessive production of reactive oxygen species, outstripping antioxidant defense systems, has been referred to as oxidant stress and has been implicated in many pathophysiological conditions in the cardiovascular system, including cigarette smoking, hypercholesterolemia, diabetes, hypertension, and heart failure.17 There are several untoward events that occur as a consequence of oxidant stress. These include oxidative modifications of DNA, lipid oxidation, modification of proteins, and activation of redox sensitive genes.18 Redox-sensitive genes are important in cardiovascular disease because many of these, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and monocyte chemoattractant protein-1 (MCP-1) are proinflammatory and play a critical role in the initiation and progression of atherosclerosis.19–21 Another significant consequence of reactive oxygen species is modification of enzyme function. An excellent example of this is the activation of matrix metalloproteinases (MMPs). These enzymes play a key role in allowing any cell to grow or migrate and are crucial in both vascular and myocardial remodeling.22–24
There is a broad body of evidence that AT1 receptor activation leads to production of reactive oxygen species in the vessel wall, in part because the AT1 receptor is linked to activation of an NADH/NADPH oxidase in vascular cells.25 This oxidase system, which has similarities to the neutrophil oxidase, is a major source of reactive oxygen species in endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts.26 Endothelial cells contain all of the subunits of the neutrophil oxidase, including gp91phox, p47phox, p67phox, p22phox, and the small GTPase rac1. In contrast, vascular smooth muscle cells contain a recently discovered protein termed NOX (for nonphagocytic oxidase), which seems to replace gp91phox as one of the membrane components.27 How the various subunits interact in vascular cells and how they produce superoxide is not well understood. It is clear, however, that the vascular NAD(P)H oxidase is responsive to hormones, metabolic factors, and mechanical forces.26,28 Besides growth factors and cytokines, angiotensin II is a principal activator of NAD(P)H oxidase expressed in vascular smooth muscle cells and fibroblasts.25,26 Angiotensin II activates the NAD(P)H oxidase via AT1 receptor activation through stimulation of intracellular signaling pathways such as arachidonic acid metabolites.29 Furthermore, angiotensin II induces a rapid translocation of the small GTPase rac1 to the cellular membrane, a prerequisite of NAD(P)H oxidase activation.30 Besides these rapid effects, angiotensin II exerts long-term alterations by enhancing the gene expression of rac1, p22phox, and NOX-1.25–27,30
The NADPH oxidase is probably not the only source of reactive oxygen species stimulated by angiotensin II. Recently, it has become apparent that endothelial nitric oxide synthase (eNOS) can produce large amounts of superoxide under certain pathophysiological conditions.31,32 One mechanism for this relates to oxidative destruction of tetrahydrobiopterin, which is a critical cofactor for eNOS function.33–35 In the absence of tetrahydrobiopterin, eNOS transfers electrons to molecular oxygen rather than to L-arginine resulting in superoxide production. Recent studies have suggested that any condition that increases superoxide production (so called "kindling radicals") in the endothelium may ultimately lead to production of a large amount of superoxide ("bonfire radicals") from uncoupled eNOS.36
Endogenous reactive oxygen species stimulated by activation of the AT1 receptor play critical roles as intracellular signaling molecules. Of the many reactive oxygen species generated in mammalian cells, hydrogen peroxide seems particularly important in cell signaling. Hydrogen peroxide is relatively stable and uncharged, allowing it to diffuse from one cell to the next. Numerous intracellular targets for hydrogen peroxide and other reactive oxygen species have been described, including the mitogen-activated protein kinase (MAPK) family, the cell survival kinase Akt, ras/rac, c-src, protein kinase C, and tyrosine phosphatases. Reactive oxygen species also modulate intracellular Ca2+ levels, altering numerous early signaling events. Many of these events have also been show to be downstream of AT1 receptor activation and are known to be redox-sensitive signaling targets.37–41
Interactions Between the AT1 Receptor, the Nitric Oxide Pathway, and Atherogenesis
One of the important consequences of increased superoxide production in response to angiotensin II is inactivation of nitric oxide.17 The two radicals superoxide and nitric oxide react with one another at a rate of 6.7x109 mol/L-1 · s-1, resulting in formation of peroxynitrite.14,15,17 Generally, the endogenous superoxide dismutases and other scavengers of superoxide keep this reaction to a minimum; however, when cellular levels of superoxide are increased, for example on angiotensin II stimulation, this reaction proceeds.42 Loss of nitric oxide via this mechanism leads to endothelial dysfunction, one of the earliest steps in the atherosclerotic process. Numerous cell culture, animal model, and clinical studies have supported the concept that AT1 receptor activation causes vascular superoxide release in vitro and in vivo leading to impaired endothelium-dependent vasodilation.25,43 In concert with these findings, inhibition of AT1 receptor activation by AT1 receptor antagonists or ACE inhibitors improves endothelial dysfunction.44–46 Loss of nitric oxide and formation of peroxynitrite promote atherosclerosis at virtually all stages of the disease.17 The earliest stages of atherosclerosis disease are associated with increased attraction and adhesion of monocytes to the endothelium.5 Inflammatory molecules such MCP-1 and VCAM-1 are critically important in this process. Importantly, expression of these is redox-sensitive and inhibited by nitric oxide.19–21,47 Angiotensin II seems to induce their production and secretion via generation of reactive oxygen species and suppression of nitric oxide.
Another phase of the atherosclerotic process is fatty streak formation, which is characterized by increased oxidation of LDL, uptake of oxLDL by macrophages, and foam cell formation, processes that are promoted by AT1 receptor activation.5,48,49 Of note, it has recently been demonstrated that expression of a receptor for oxidized LDL, known as the LOX receptor, is dramatically increased by AT1 receptor activation.48 In addition, oxLDL uptake may be also enhanced via angiotensin II effects on the cellular proteoglycan content.49
Plaque formation is propagated by migration and proliferation of vascular smooth muscle cells. Again, there is ample evidence suggesting that the oxidant stress induced by angiotensin II plays a major role in stimulating growth and migration of vascular smooth muscle cells.5,17
Finally, plaque rupture is the result of increased lipid deposition, inflammatory events, apoptosis, and accelerated matrix degradation within the preformed vascular lesion.5 Besides the enhanced lipid deposition, AT1 receptor activation initiates inflammatory processes such as interleukin-6 production.50 Vascular smooth muscle cell apoptosis, which seems to be a prelude to plaque rupture, is induced via angiotensin II and prevented by AT1 receptor blockade.10,11 In keeping with these observations, angiotensin II increases MMP activity, resulting in plaque degradation and ultimately rupture.24 Interestingly, recent reports have suggested that angiotensin II modulates hematopoiesis within the bone marrow. Monocyte CD11b expression is enhanced, ultimately impacting on monocyte-endothelial interactions.7 To date, it is not clear whether endothelial dysfunction during early atherogenesis resembles the pathological state of endothelial cells shortly before or during plaque rupture. Within this review, both syndromes are referred to as endothelial dysfunction.
To summarize the above information, angiotensin II, via its actions on the AT1 receptor, promotes the atherosclerotic process at virtually all stages of the disease (Figure 1). These actions of angiotensin II are at least in part mediated by reactive oxygen species.
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Perspectives
Atherosclerosis is clearly caused by both a genetic predisposition to the disease and a variety of exogenous risk factors. Whereas the epidemiological correlation between risk factors and atherosclerosis has been established, the molecular events initiated by those risk factors that ultimately lead to atherosclerosis remain poorly understood. It is apparent from the data accumulated to date, that one possible link between risk factors and the development of vascular disease is in fact AT1 receptor activation. AT1 receptor–evoked oxidative stress has been implicated in all states of atherosclerosis, starting with the development of endothelial dysfunction and ultimately leading to plaque rupture and occlusion of the diseased vessel. Besides the traditional effects of AT1 receptor activation, such as vasoconstriction, water and salt homeostasis, and neurohumoral activation, the interaction of the AT1 receptor with radical-producing systems such as the NAD(P)H oxidase and the eNOS enzyme is thought to be a key event in atherogenesis.
AT1 receptor antagonists or ACE inhibitors normalize oxidative stress and endothelial dysfunction and reduce the progression of atherosclerosis.44–46 ACE inhibitors are known to retard the progression of atherosclerosis and heart failure.51–53 In men suffering from coronary heart disease, ACE inhibitors improve endothelial dysfunction and reduce rate of death from cardiovascular causes.54 Recent studies in hypertensive and atherosclerotic individuals showed that AT1 receptor antagonists improved endothelial dysfunction, suggesting that these drugs, like ACE inhibitors, benefit vascular function.45,46
Thus, AT1 receptor–elicited oxidative stress has been identified as one key event of the atherosclerotic disease process. Therefore, ACE inhibitors as well as AT1 receptor antagonists are potent antiatherosclerotic drugs, which is predominately related to their antioxidative properties. However, large-scale investigations will have to show that AT1 receptor antagonists not only decrease free radicals and improve endothelial dysfunction but also inhibit atherosclerosis-associated mortality and morbidity.
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References |
|---|
|
TopIntroductionAT1 Receptor and Oxidative...References |
|---|
1. Peach MJ. Renin-angiotensin system: biochemistry and mechanism of action. Physiol Rev. 1977; 57: 313–370.
2.
Griendling KK, Murphy TJ, Alexander RW. Molecular biology of the renin-angiotensin system. Circulation. 1993; 87: 1816–1828.
3. Timmermans PB, Wong PC, Chiu AT, et al. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev. 1993; 45: 205–251.[Medline] [Order article via Infotrieve]
4. Griendling KK, Lassègue B, Alexander RW. Angiotensin receptors and their therapeutic implications. Annu Rev Pharmacol Toxicol. 1996; 36: 281–306.[Medline] [Order article via Infotrieve]
5.
Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.
6.
Vaughan DE. AT1 receptor blockade, and atherosclerosis, hopeful insights into vascular protection. Circulation. 2000; 101: 1496–1497.
7. Strawn WB, Dean RH, Ferrario CM. Novel mechanisms linking angiotensin II and early atherogenesis. JRAAS. 2000; 1: 11–17.
8. Unger T. The angiotensin type 2 receptor: variations on an enigmatic theme. J Hypertens. 1999; 17: 1775–1786.[CrossRef][Medline] [Order article via Infotrieve]
9.
Carey RM, Wang ZQ, Siragy HM. Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function. Hypertension. 2000; 35: 155–163.
10. Mallat Z, Tedgui A. Apoptosis in the vasculature: mechanisms and functional importance. Br J Pharmacol. 2000; 130: 947–962.[CrossRef][Medline] [Order article via Infotrieve]
11. Lemay J, Hamet P, de Blois D. Losartan-induced apoptosis as a novel mechanism for the prevention of vascular lesion formation after injury. JRAAS. 2000; 1: 46–50.
12. Dzau VJ. Mechanism of protective effects of ACE inhibition on coronary artery disease. Eur Heart J. 1998; 19: J2–J6.
13.
Romero JC, Reckelhoff JF. State-of-the-art lecture: role of angiotensin and oxidative stress in essential hypertension. Hypertension. 1999; 34: 943–949.
14. Babior BM. Phagocytes and oxidative stress. Am J Med. 2000; 109: 33–44.[CrossRef][Medline] [Order article via Infotrieve]
15. Hensley K, Robinson KA, Gabbita SP, et al. Reactive oxygen species, cell signaling, and cell injury. Free Radic Biol Med. 2000; 28: 1456–1462.[CrossRef][Medline] [Order article via Infotrieve]
16.
Griendling KK, Harrison DG. Dual role of reactive oxygen species in vascular growth. Circ Res. 1999; 85: 562–563.
17. Harrison DG. Endothelial function and oxidant stress. Clin Cardiol. 1997; 20 (suppl II): 11–17.[Medline] [Order article via Infotrieve]
18. Patel RP, Moellering D, Murphy-Ullrich J, et al. Cell signaling by reactive nitrogen and oxygen species in atherosclerosis. Free Radic Biol Med. 2000; 28: 1780–1794.[CrossRef][Medline] [Order article via Infotrieve]
19.
Pueyo ME, Gonzalez W, Nicoletti A, et al. Angiotensin II stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-
B activation induced by intracellular oxidative stress. Arterioscler Thromb Vasc Biol. 2000; 20: 645–651.
20.
Usui M, Egashira K, Tomita H, et al. Important role of local angiotensin II activity mediated via type 1 receptor in the pathogenesis of cardiovascular inflammatory changes induced by chronic blockade of nitric oxide synthesis in rats. Circulation. 2000; 101: 305–310.
21.
Luft FC, Mervaala E, Muller DN, et al. Hypertension-induced end-organ damage: a new transgenic approach to an old problem. Hypertension. 1999; 33: 212–218.
22.
Siwik DA, Pagano PJ, Colucci WS. Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. Am J Physiol Cell Physiol. 2001; 280: C53–C60.
23.
Janiszewski M, Pasqualucci CA, Souza LC, et al. Oxidized thiols markedly amplify the vascular response to balloon injury in rabbits through a redox active metal-dependent pathway. Cardiovasc Res. 1998; 39: 327–338.
24. Funck RC, Wilke A, Rupp H, et al. Regulation and role of myocardial collagen matrix remodeling in hypertensive heart disease. Adv Exp Med Biol. 1997; 432: 35–44.[Medline] [Order article via Infotrieve]
25.
Griendling KK, Minieri CA, Ollerenshaw JD, et al. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured smooth muscle cells. Circ Res. 1994; 74: 1141–1148.
26.
Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res. 2000; 86: 494–501.
27. Suh YA, Arnold RS, Lassegue B, et al. Cell transformation by the superoxide-generating oxidase Mox1. Nature. 1999; 401: 79–82.[CrossRef][Medline] [Order article via Infotrieve]
28. Meyer JW, Schmitt ME. A central role for the endothelial NAD(P)H oxidase in atherosclerosis. FEBS Lett. 2000; 472: 1–4.[CrossRef][Medline] [Order article via Infotrieve]
29.
Griendling KK, Sorescu D, Lassegue B, et al. Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology. Arterioscler Thromb Vasc Biol. 2000; 20: 2175–2183.
30.
Wassmann S, Laufs U, Baumer AT, et al. Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1-receptor expression an rac1 GTPase. Mol Pharmacol. 2001; 59: 646–654.
31.
Wang W, Wang S, Yan L, et al. Superoxide production and reactive oxygen species signaling by endothelial nitric-oxide synthase. J Biol Chem. 2000; 275: 16899–16903.
32.
Shinozaki K, Nishio Y, Okamura T, et al. Oral administration of tetrahydrobiopterin prevents endothelial dysfunction and vascular oxidative stress in the aortas of insulin-resistant rats. Circ Res. 2000; 87: 566–573.
33. Shinozaki K, Kashiwagi A, Nishio Y, et al. Abnormal biopterin metabolism is a major cause of impaired endothelium-dependent relaxation through nitric oxide/O2-imbalance in insulin-resistant rat aorta. Diabetes. 1999; 48: 2437–2445.[Abstract]
34.
Xia Y, Tsai AL, Berka V, et al. Superoxide generation from endothelial nitric-oxide synthase: a Ca2+/calmodulin-dependent and tetrahydrobiopterin regulatory process. J Biol Chem. 1998; 273: 25804–25808.
35.
Vasquez-Vivar J, Kalyanaraman B, Martasek P, et al. Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci U S A. 1998; 95: 9220–9225.
36.
Hink U, Li H, Mollnau H, et al. Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res. 2001; 88: e14–e22.
37. Hsieh HJ, Cheng CC, Wu ST, et al. Increase of reactive oxygen species in endothelial (ROS) cells by shear flow and involvement of ROS in shear-induced c-fos expression. J Cell Physiol. 1998; 175: 156–162.[CrossRef][Medline] [Order article via Infotrieve]
38.
Abe J, Berk BC. Fyn and JAK2 mediate RAS activation by reactive oxygen species. J Biol Chem. 1999; 274: 21003–21010.
39.
Kawakami M, Okabe E. Superoxide anion radical-triggered Ca2+ release from cardiac sarcoplasmatic reticulum through ryanodine receptor Ca2+ channel. Mol Pharmacol. 1998; 53: 497–503.
40.
Ushio-Fukai M, Wayne Alexander R, Akers M, et al. p38 Mitogen-activated protein kinase is a critical component of the redox-sensitive signaling pathways activated by angiotensin II. J Biol Chem. 1998; 273: 15022–15029.
41.
Ushio-Fukai M, Alexander WR, Akers M, et al. Reactive oxygen species mediate the activation of Akt/protein kinase B by angiotensin II in vascular smooth muscle cells. J Biol Chem. 1999; 274: 22699–22704.
42.
Tomasian D, Keaney JF, Vita JA. Antioxidants and the bioactivity of endothelium-derived nitric oxide. Cardiovasc Res. 2000; 47: 426–435.
43.
Laursen JB, Rajagopalan S, Galis Z, et al. Role of superoxide in angiotensin II–induced but not catecholamine-induced hypertension. Circulation. 1997; 95: 588–593.
44.
Mancini JGB, Henry GC, Macaya C, et al. Angiotensin converting enzyme inhibition with quinapril improves endothelial dysfunction in patients with coronary artery disease. Circulation. 1996; 94: 258–265.
45.
Prasad A, Tupas-Habib T, Schenke WH, et al. Acute and chronic angiotensin-1 receptor antagonism reverses endothelial dysfunction in atherosclerosis. Circulation. 2000; 101: 2349–2354.
46.
Schiffrin EL, Park JB, Intengan HD, et al. Correction of arterial structure and endothelial dysfunction in human essential hypertension by the angiotensin receptor antagonist losartan. Circulation. 2000; 101: 1653–1659.
47.
Kranzhöfer R, Browatzki M, Schmidt J, et al. Angiotensin II activates the proinflammatory transcription factor nuclear factor-B in human monocytes. Biochem Biophys Res Commun. 1999; 257: 826–828.[CrossRef][Medline]
[Order article via Infotrieve]
48.
Morawietz H, Rueckschloss U, Niemann B, et al. Angiotensin II induces LOX-1, the human endothelial receptor for oxidized low-density lipoprotein. Circulation. 1999; 100: 899–902.
49. Keidar S, Attias J. Angiotensin II injection into mice increases the uptake of oxidized LDL by their macrophages via a proteoglycan-mediated pathway. Biochem Biophys Res Commun. 1997; 239: 63–67.[CrossRef][Medline] [Order article via Infotrieve]
50.
Schieffer B, Schieffer E, Hilfiker-Kleiner D, et al. Expression of angiotensin II and interleukin-6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability. Circulation. 2000; 101: 1372–1378.
51. Pitt B. The potential use of angiotensin-converting enzyme inhibitors in patients with hyperlipidemia. Am J Cardiol. 1997; 79: 24–28.
52. Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet. 1993; 342: 821–828.[Medline] [Order article via Infotrieve]
53. Consensus Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (Consensus). N Engl J Med. 1987; 316: 1429–1435.[Abstract]
54.
Heart Outcome Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme, ramipril, on cardiovascular events. N Engl J Med. 2000; 342: 145–153.
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S. Wassmann, T. Czech, M. van Eickels, I. Fleming, M. Bohm, and G. Nickenig Inhibition of Diet-Induced Atherosclerosis and Endothelial Dysfunction in Apolipoprotein E/Angiotensin II Type 1A Receptor Double-Knockout Mice Circulation, November 9, 2004; 110(19): 3062 - 3067. [Abstract] [Full Text] [PDF]
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G. Nickenig Should Angiotensin II Receptor Blockers and Statins Be Combined? Circulation, August 24, 2004; 110(8): 1013 - 1020. [Full Text] [PDF]
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K. K. Koh, J. W. Son, J. Y. Ahn, D. S. Kim, D. K. Jin, H. S. Kim, S. H. Han, Y.-H. Seo, W.-J. Chung, W. C. Kang, et al. Simvastatin Combined With Ramipril Treatment in Hypercholesterolemic Patients Hypertension, August 1, 2004; 44(2): 180 - 185. [Abstract] [Full Text] [PDF]
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I. Jialal, S. Devaraj, and S. K. Venugopal C-Reactive Protein: Risk Marker or Mediator in Atherothrombosis? Hypertension, July 1, 2004; 44(1): 6 - 11. [Abstract] [Full Text] [PDF]
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 C. Delles, G. Michelson, J. Harazny, S. Oehmer, K. F. Hilgers, and R. E. Schmieder Impaired Endothelial Function of the Retinal Vasculature in Hypertensive Patients Stroke, June 1, 2004; 35(6): 1289 - 1293. [Abstract] [Full Text] [PDF]
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D. N. Granger, T. Vowinkel, and T. Petnehazy Modulation of the Inflammatory Response in Cardiovascular Disease Hypertension, May 1, 2004; 43(5): 924 - 931. [Abstract] [Full Text] [PDF]
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S. Wassmann, M. Stumpf, K. Strehlow, A. Schmid, B. Schieffer, M. Bohm, and G. Nickenig Interleukin-6 Induces Oxidative Stress and Endothelial Dysfunction by Overexpression of the Angiotensin II Type 1 Receptor Circ. Res., March 5, 2004; 94(4): 534 - 541. [Abstract] [Full Text] [PDF]
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R. D. Roghair, F. S. Lamb, K. A. Bedell, O. M. Smith, T. D. Scholz, and J. L. Segar Late-gestation betamethasone enhances coronary artery responsiveness to angiotensin II in fetal sheep Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2004; 286(1): R80 - R88. [Abstract] [Full Text]
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J. Hwang, M. H. Ing, A. Salazar, B. Lassegue, K. Griendling, M. Navab, A. Sevanian, and T. K. Hsiai Pulsatile Versus Oscillatory Shear Stress Regulates NADPH Oxidase Subunit Expression: Implication for Native LDL Oxidation Circ. Res., December 12, 2003; 93(12): 1225 - 1232. [Abstract] [Full Text] [PDF]
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M.-S. Zhou, A. G. Adam, E. A. Jaimes, and L. Raij In Salt-Sensitive Hypertension, Increased Superoxide Production Is Linked to Functional Upregulation of Angiotensin II Hypertension, November 1, 2003; 42(5): 945 - 951. [Abstract] [Full Text] [PDF]
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M. C. Chappell, P. E. Gallagher, D. B. Averill, C. M. Ferrario, and K. B. Brosnihan Estrogen or the AT1 Antagonist Olmesartan Reverses the Development of Profound Hypertension in the Congenic mRen2.Lewis Rat Hypertension, October 1, 2003; 42(4): 781 - 786. [Abstract] [Full Text] [PDF]
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 K. K. Koh, J. Y. Ahn, S. H. Han, D. S. Kim, D. K. Jin, H. S. Kim, M.-S. Shin, T. H. Ahn, I. S. Choi, and E. K. Shin Pleiotropic effects of angiotensin II receptor blocker in hypertensive patients J. Am. Coll. Cardiol., September 3, 2003; 42(5): 905 - 910. [Abstract] [Full Text] [PDF]
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B. Lassegue and R. E. Clempus Vascular NAD(P)H oxidases: specific features, expression, and regulation Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2003; 285(2): R277 - R297. [Abstract] [Full Text] [PDF]
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S. P. Didion and F. M. Faraci Angiotensin II Produces Superoxide-Mediated Impairment of Endothelial Function in Cerebral Arterioles Stroke, August 1, 2003; 34(8): 2038 - 2042. [Abstract] [Full Text] [PDF]
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J. R. Privratsky, L. E. Wold, J. R. Sowers, M. T. Quinn, and J. Ren AT1 Blockade Prevents Glucose-Induced Cardiac Dysfunction in Ventricular Myocytes: Role of the AT1 Receptor and NADPH Oxidase Hypertension, August 1, 2003; 42(2): 206 - 212. [Abstract] [Full Text] [PDF]
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 A. Ceriello New Insights on Oxidative Stress and Diabetic Complications May Lead to a "Causal" Antioxidant Therapy Diabetes Care, May 1, 2003; 26(5): 1589 - 1596. [Abstract] [Full Text] [PDF]
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C.-H. Wang, S.-H. Li, R. D. Weisel, P. W.M. Fedak, A. S. Dumont, P. Szmitko, R.-K. Li, D. A.G. Mickle, and S. Verma C-Reactive Protein Upregulates Angiotensin Type 1 Receptors in Vascular Smooth Muscle Circulation, April 8, 2003; 107(13): 1783 - 1790. [Abstract] [Full Text] [PDF]
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 S. H. Wilson, A. R. Chade, A. Feldstein, T. Sawamura, C. Napoli, A. Lerman, and L. O. Lerman Lipid-lowering-independent effects of simvastatin on the kidney in experimental hypercholesterolaemia Nephrol. Dial. Transplant., April 1, 2003; 18(4): 703 - 709. [Abstract] [Full Text] [PDF]
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M. Tepel, M. van der Giet, M. Statz, J. Jankowski, and W. Zidek The Antioxidant Acetylcysteine Reduces Cardiovascular Events in Patients With End-Stage Renal Failure: A Randomized, Controlled Trial Circulation, February 25, 2003; 107(7): 992 - 995. [Abstract] [Full Text] [PDF]
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 U. Laufs, O. Adam, K. Strehlow, S. Wassmann, C. Konkol, K. Laufs, W. Schmidt, M. Bohm, and G. Nickenig Down-regulation of Rac-1 GTPase by Estrogen J. Biol. Chem., February 14, 2003; 278(8): 5956 - 5962. [Abstract] [Full Text] [PDF]
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F. S. Gragasin, Y. Xu, I. A. Arenas, N. Kainth, and S. T. Davidge Estrogen Reduces Angiotensin II-Induced Nitric Oxide Synthase and NAD(P)H Oxidase Expression in Endothelial Cells Arterioscler. Thromb. Vasc. Biol., January 1, 2003; 23(1): 38 - 44. [Abstract] [Full Text] [PDF]
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 R. De Caterina and C. Manes Inflammation in early atherogenesis: impact of ACE inhibition Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A15 - A24. [Abstract] [PDF]
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H. Cai, Z. Li, S. Dikalov, S. M. Holland, J. Hwang, H. Jo, S. C. Dudley Jr., and D. G. Harrison NAD(P)H Oxidase-derived Hydrogen Peroxide Mediates Endothelial Nitric Oxide Production in Response to Angiotensin II J. Biol. Chem., December 6, 2002; 277(50): 48311 - 48317. [Abstract] [Full Text] [PDF]
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 M. Volpe, C. Savoia, P. De Paolis, B. Ostrowska, D. Tarasi, and S. Rubattu The Renin-Angiotensin System as a Risk Factor and Therapeutic Target for Cardiovascular and Renal Disease J. Am. Soc. Nephrol., November 1, 2002; 13(90003): S173 - 178. [Abstract] [Full Text]
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U. Landmesser, H. Cai, S. Dikalov, L. McCann, J. Hwang, H. Jo, S. M. Holland, and D. G. Harrison Role of p47phox in Vascular Oxidative Stress and Hypertension Caused by Angiotensin II Hypertension, October 1, 2002; 40(4): 511 - 515. [Abstract] [Full Text] [PDF]
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