doi: 10.1161/CIRCRESAHA.107.148338
© 2007 American Heart Association, Inc.
Review |
Angiotensin-Converting Enzyme and Vascular Remodeling
From the Department of Pathology, Maastricht University, Cardiovascular Research Institute Maastricht, The Netherlands.
Correspondence to Sylvia Heeneman, Maastricht University, Department of Pathology, Cardiovascular Research Institute Maastricht, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands. E-mail s.heeneman{at}path.unimaas.nl
This Review is part of a thematic series on Angiotensin-Converting Enzyme, which includes the following articles:
Six Truisms Concerning ACE and the Renin-Angiotensin System Educed From the Genetic Analysis of Mice
Angiotensin-Converting Enzyme II in the Heart and the Kidney
Signaling by the Angiotensin-Converting Enzyme
ACE Polymorphisms
Angiotensin-Converting Enzyme and Vascular Remodeling
Kathy Griendling and Rudi Busse Editors
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Abstract |
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 Top Abstract IntroductionVascular Effects of ACE...ACE and Neointimal...ACE and Vascular Remodeling...ACE and AtherosclerosisACE and Aneurysm FormationAngiotensin-Converting Enzyme 2ConclusionReferences |
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Vascular remodeling is the result of a close interplay of changes in vascular tone and structure. In this review, the role of angiotension-converting enzyme (ACE) and the impact of ACE inhibition on vascular remodeling processes during vascular injury and restenosis, hypertension, atherosclerosis, and aneurysm formation are discussed. The role of ACE and angiotensin II (Ang II) in neointimal thickening has been firmly established by animal studies and is mediated by Ang II type 1 (AT1) receptor signaling events via monocyte chemoattractant protein-1 and NAD(P)H oxidase. ACE and Ang II are involved in the remodeling of large and resistance arteries during hypertension; here, cell proliferation and matrix remodeling are also regulated by signaling events downstream of the AT1 receptor. In atherosclerosis, Ang II is involved in the inflammatory and tissue response, mediated by various signaling pathways downstream of the AT1 receptor. Although ACE inhibition has been shown to inhibit atherosclerotic processes in experimental animal models, results of large clinical trials with ACE inhibitors were not conclusive. Remodeling of vessel dimensions and structure during aneurysm formation is counteracted by ACE inhibition. Here, a direct effect of ACE inhibitors on matrix metalloproteinase activity has to be considered as part of the working mechanism. The role of ACE2 in vascular remodeling has yet to be established; however, ACE2 has been shown to be associated with vascular changes in hypertension and atherosclerosis.
Key Words: vascular remodeling • angiotensin-converting enzyme • hypertension • atherosclerosis • restenosis
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Introduction |
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TopAbstractIntroductionVascular Effects of ACE...ACE and Neointimal...ACE and Vascular Remodeling...ACE and AtherosclerosisACE and Aneurysm FormationAngiotensin-Converting Enzyme 2ConclusionReferences |
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The vascular wall is continuously exposed to hemodynamic forces such as luminal pressure and shear stress. Alterations in these forces, either physiological or pathological, lead to functional and/or structural alterations of the vascular wall. Acute changes in hemodynamic forces can modify vessel diameter. Chronic changes in hemodynamic forces result in structural alterations of the vessel wall, indicated by changes in wall diameter and thickness. In addition, changes in vascular structure are not solely determined by hemodynamic forces,1 and a role for inflammatory responses and changes in extracellular matrix components has been suggested.2 Structural changes of the medial layer of the vascular wall during hypertension were termed "remodeling"3–6 and subsequently translated to other vascular pathologies (Figure 1). The schematic representation is slightly adapted because in these pathologies, structural alterations of the intimal layer of the vascular wall contribute to total vessel wall mass. Thus, outward remodeling during atherosclerosis compensates for the plaque growth and postpones progression to flow-limiting stenosis, whereas during restenosis, intimal hyperplasia and constrictive remodeling result in luminal narrowing. It has been generally accepted and acknowledged that vascular remodeling is an important determinant in vascular pathologies.2,7,8
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Remodeling of the vascular wall is the result of changes in both the cellular and noncellular components. Depending on the pathological process (Figure 1), smooth muscle cell (SMC) growth and migration, endothelial cell dysfunction, inflammation, extracellular matrix synthesis, or degradation are present.
Patients with essential hypertension are routinely treated with calcium channel blockers, diuretics, and angiotensin-converting enzyme (ACE) inhibitors. Several of these therapeutic agents are capable of (partially) correcting the remodeling of small arteries and arterioles that are seen in these patients,9 and this is particularly true for the ACE inhibitors. ACE plays a key role in the renin–angiotensin system (RAS), as it generates the active octapeptide angiotensin (Ang) II from the decapeptide angiotension I. Ang II is the most well-known active peptide of the RAS, with very diverse functions. It is a potent vasoconstrictor but is also involved in inflammatory processes, cell growth, and matrix deposition and can lead to a prothrombotic state (reviewed elsewhere10). Given these functions, Ang II is considered a regulatory factor in the changes in wall structure and function during vascular remodeling.
In this review, after a short introduction on the effects of ACE on vascular function and signaling pathways, the role of ACE and the impact of ACE inhibition on vascular remodeling are discussed. Because "remodeling of the vessel wall" has diverse characteristics in different vascular pathologies, the role of ACE is discussed separately for remodeling during neointimal thickening/restenosis, hypertension, atherosclerosis, and aneurysm formation.
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Vascular Effects of ACE and Downstream Signaling Pathways |
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TopAbstractIntroductionVascular Effects of ACE...ACE and Neointimal...ACE and Vascular Remodeling...ACE and AtherosclerosisACE and Aneurysm FormationAngiotensin-Converting Enzyme 2ConclusionReferences |
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The vascular effects of ACE are summarized in Table 1. Ang II, produced locally by endothelial ACE, is one of the key substances that affects endothelial function (or dysfunction). Ang II is a potent vasoconstrictor and is also able to induce other vasoconstrictors (see Table 1). In addition, ACE reduces vasodilation via degradation of bradykinin, a potent vasodilator (direct and indirect through reduced release of endothelium-derived NO and prostacyclin). This dual effect of ACE, generation of a vasoconstrictor and degradation of a vasodilator, is important in the regulation of vascular tone by the RAS. These effects of ACE are reflected by the signaling pathways that are activated by Ang II and bradykinin (Figure 2). Although several angiotensin receptors have been described, this review focuses on the physiological and pathological effects during vascular remodeling that are mediated via the Ang II type 1 (AT1) receptor. The AT1 receptor signals through small GTP-binding proteins. Each of these small G proteins has key roles in specific cell functions. The Ras family regulates gene expression, the Rho family regulates cytoskeletal reorganization and gene expression, and the Rac family controls membrane ruffling and cell spreading.11,12 Figure 2 shows a selection of the up- and downstream signaling pathways of these small G proteins in relation to the AT1 receptor. Upstream are several tyrosine kinases, such as src and JAK2/Tyk, which have been shown to be pivotal to Ang II signaling pathways.13 Downstream are the mitogen-activated kinases (MAPK) and signal transducers and activators of transcription (STATs).11 Through these signaling cascades, Ang II initiates tissue remodeling via induction of SMC hypertrophy, hyperplasia, and migration and extracellular matrix production and synthesis of proinflammatory mediators. An important costimulatory event is the AT1 receptor–dependent activation of NAD(P)H oxidase by Ang II.14,15 This produces reactive oxygen species (ROS) (and reduces NO bioavailability) and initiates myriad other signaling events and activation of transcription factors such as Nuclear Factor
B and Activator Protein-1 (Figure 2). These transcription factors can induce multiple mediators of leukocyte recruitment, such as expression of selectins (E- and P-selectin) and integrins (ß-2, 
-4 integrin, and VLA-4)16–18 and proinflammatory molecules such as monocyte chemoattractant protein 1 and interleukin (IL)-6.19,20 In SMCs, Ang II can also directly activate nuclear factor B, most likely via degradation of IBs.21
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Finally, ACE itself is also linked to a signaling cascade. In endothelial cells, binding of ACE inhibitors to ACE increases casein kinase 2–mediated phosphorylation of ACE, which activates ACE-associated JNK, most likely through mitogen-activated kinase kinase 7 (MKK7). JNK phosphorylates c-Jun and via activator protein-1, ACE, and cyclooxygenase-2 are transcribed (reviewed elsewhere22).
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ACE and Neointimal Thickening/Restenosis |
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TopAbstractIntroductionVascular Effects of ACE...ACE and Neointimal...ACE and Vascular Remodeling...ACE and AtherosclerosisACE and Aneurysm FormationAngiotensin-Converting Enzyme 2ConclusionReferences |
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In the balloon-injured rat carotid, the developing neointima expressed high levels of ACE.23 In another model of cuff-induced neointima formation in the femoral artery of mice, ACE expression was again increased in the neointimal, medial, and periadventitial area of the cuffed artery.24 The effect of ACE on vascular remodeling was first established by a study of Morishita et al,25 in which in vivo gene transfer of ACE in a normal, uninjured rat carotid artery resulted in increased wall-to-lumen ratios, indicative of the development of vascular hypertrophy. A follow-up study by the same group, using an antisense oligonucleotide against ACE in a rat vascular injury model, showed a significant decrease in neointima formation.26
The mechanisms by which ACE and Ang II can induce neointimal thickening or restenosis are only partly elucidated. The AT1 receptor has been shown to play a central role. Neointimal AT1 receptor expression increased in the rat model of carotid injury, even 24 weeks after injury. AT1 receptor blockade inhibited neointimal thickening and collagen and elastin accumulation.27 In monkeys and rabbits, AT1 receptor blockade also reduced in-stent restenosis, oxidative stress, proinflammatory factors (MCP-1, IL-1ß, and tumor necrosis factor-) and NAD(P)H oxidase subunits (p22-phox, gp99-phox). These molecules are downstream of the AT1 receptor (Figure 2), suggesting that AT1 receptor signaling is involved in neointimal formation.28 Finally, protein kinase C is downstream of the AT1 receptor and one of its iso-forms, protein kinase C-
was shown to be essential in normal and Ang II–accelerated neointimal growth after vascular injury. Inhibition of protein kinase C- attenuated medial cellularity and expression of inflammatory mediators.29
ACE inhibitors have been shown to inhibit neointima formation in response to vascular injury in several models and species, such as in balloon-induced vascular injury in rats30 and guinea pig,31 in allograft-induced intima formation in rats,32 and cuff-induced neointima formation in mice.24,33 Several follow-up studies in these models showed that the favorable effects of ACE inhibition could be attributed, in part, to the bradykinin/endothelial NO synthase pathway and/or oxidative stress/NAD(P)H pathway.33–35
However, not all studies showed a beneficial effect of ACE inhibition after vascular injury. In rabbits, ACE inhibition with cilazapril did not reduce or prevent neointima formation after injury to the carotid artery,31 and similar negative results were found in baboons.36 Moreover, in large clinical trials (MERCATOR, MARCATOR), low antihypertensive doses of cilazapril did not prevent restenosis nor had favorable effects on overall clinical outcome after percutaneous transluminal coronary angioplasty (PTCA).37,38 These studies suggest that inhibition of ACE is ineffective in inhibiting restenosis in patients following PTCA.
The lack of effect of ACE inhibition on restenosis in patients after PTCA was unexpected, and the possible causes for this discrepancy have been discussed extensively in literature. Firstly, the animal models used are different from the human situation. In the rat carotid injury model, "restenosis" is a misnomer and actually a neointima formed after an injury to a normal vessel, whereas in the human situation, a significant plaque burden leading to stenosis is already present before the injury.39 Thus, fundamental differences in pathophysiology could explain the discrepancy in the outcome of clinical trials and preclinical studies in animal models for ACE inhibition in restenosis. Secondly, there may be a dose effect. Rakugi et al showed that there was a dissociation of the ability of an ACE inhibitor to decrease blood pressure and circulating ACE activity from its ability to inhibit tissue ACE. It was shown that the dose necessary to inhibit neointima formation was higher than the hypotensive dose. Thus, higher doses of ACE inhibitors may be needed to inhibit tissue ACE and prevent restenosis in patients.40 Thirdly, there is a remarkable species variation in the activity of non–ACE-dependent conversion of Ang I to Ang II.41 It has become clear that ACE is not the only enzyme that can generate Ang II. In studies by Okunishi et al,42,43 evidence was presented that in blood vessels of various species, a unique enzyme was present that converts Ang I in Ang II. This enzyme was later identified as chymase. In a follow-up study, Okunishi et al showed that vascular expression of chymase differed between species. In human arterial strips, treatment with captopril blocked 30% to 40% of the conversion of Ang I to Ang II, whereas inhibition of chymase by chymostatin blocked 60% of Ang II generation. In rabbit arteries, however, captopril induced >90% inhibition and chymostatin had minimal effect.44 Also, Jin et al reported that the ratio of ACE- and chymase-dependent Ang II formation is even different in various blood vessels of the same species.45 This site specificity could also explain the fact that studies in humans showed an exclusive ACE dependency of local Ang II generation in the forearm,46 although the study by Okunishi et al described above showed a 60% chymase dependency in human gastroepiploic arterial strips.44
In conclusion, ACE inhibition was not effective in inhibiting restenosis in patients after PTCA. Although several issues still need to be resolved (eg, fundamental differences between animal models and human disease; species- and vessel-type-specific expression of chymase; and dosage of ACE inhibitor), the results of clinical trials were unexpected to some extent and do not advocate the use of ACE inhibitors in these patients. This does not exclude the important role of Ang II in the development of restenosis. Experimental studies have shown that the AT1 receptor and downstream pathways are involved in neointima formation; moreover, selective angiotensin receptor blockers may be effective in preventing restenosis in patients with complex lesions. In the Val-PREST trial, it was shown that restenosis was only 19% in valsartan-treated patients, compared with 39% in the control group.47
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ACE and Vascular Remodeling During Hypertension |
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TopAbstractIntroductionVascular Effects of ACE...ACE and Neointimal...ACE and Vascular Remodeling...ACE and AtherosclerosisACE and Aneurysm FormationAngiotensin-Converting Enzyme 2ConclusionReferences |
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Remodeling of the Large Conduit Arteries
During essential hypertension, the large arteries exhibit an increased lumen size, a thickened media with increased collagen deposition, and decreased compliance.4,48,49 The thickening of the arterial wall is considered to be one of the main compensatory mechanisms to preserve circumferential wall stress.50 In hypertensive patients, carotid pulse pressure was a strong independent determinant of carotid artery enlargement and wall hypertrophy, whereas mean blood pressure and brachial pulse pressure were not, indicating the strong influence of local pulsatile mechanical load.51 The outward hypertrophic vascular remodeling is progressive because it increased with age in the carotid artery of patients with untreated essential hypertension.52 Hypertension is clearly associated with increased cardiovascular morbidity and mortality, and it is thought that vascular hypertrophy leads to increased atherosclerotic disease at arterial sites such as the carotid artery.53
The RAS has been clearly implicated in hypertension-induced large artery hypertrophy. Ang II–induced SMC hypertrophy and collagen deposition (Table 1) have been shown in hypertensive animal models.54,55 More recently, attention was also directed toward the effect of inflammation and endothelial dysfunction during hypertension. It is likely that the RAS, and more specifically Ang II, is also involved in cytokine excretion, inflammatory cell adhesion, and endothelial dysfunction during hypertension-induced remodeling of the large arteries (Table 1 and Kakar and Lip56).
There is conflicting evidence regarding the increase in ACE expression in the vascular wall during experimental hypertension. Most reports have shown an increase in vascular ACE expression in 2-kidney, 1-clip–induced hypertension57–59 and spontaneous hypertensive rats (SHRs),60 although Jandeleit et al did not find altered ACE concentrations in the resistance arteries of SHRs.61 However, ACE inhibitors have been shown to induce a significant regression in large artery hypertrophy both in animals with hypertension54,55,62 and hypertensive patients.63–65 These studies mainly focused on effects on the large elastic conduit arteries, but Girard et al showed that smaller, more muscular arteries also benefited from ACE inhibition. In this study, it was shown that long-term ACE inhibition by perindopril not only improved carotid artery compliance but also reduced radial artery hypertrophy.66 Also, Armentano et al recently showed that ACE inhibition resulted in improved wall energetics and wall stress by reducing SMC activation and vessel wall remodeling. These findings suggests that ACE inhibition also protects vascular function and is able to reduce extra load on the heart.67
ACE and Remodeling of Resistance Arteries During Hypertension
In contrast to the outward hypertrophic remodeling of the large arteries during hypertension, small (resistance) arteries exhibit a smaller lumen and external diameter, a normal or increased media thickness and an increased media-to-lumen ratio.49 SMC hypertrophy or hyperplasia may be present depending on the species, vascular bed, or severity of the disease. In hypertensive patients, a rearrangement of SMCs around a smaller lumen was shown,68 but in patients with renovascular hypertension, remodeling of resistance arteries resulting from SMC hypertrophy was also present.69 Changes in extracellular matrix content are also involved in this remodeling, as collagen and fibronectin deposits were found in the resistance arteries of experimental models and patients with hypertension.70 Remodeling of the resistance arteries during hypertension may be one of the first signs of organ damage found in mild hypertension in humans. It preceded the development of left ventricular hypertrophy and thickening of the intima–media of the large conduit arteries.71
Small artery remodeling is involved in the clinical complications of hypertension, such as stroke, nephroangiosclerosis, and myocardial infarction.49 Pulse pressure was shown to be the most important determinant of small artery remodeling in elderly patients with mild essential hypertension.71 In contrast, in younger patients, small artery remodeling correlated with diastolic pressure. Thus with age, the cause of small artery remodeling changes and pulse pressure becomes an important determinant of increased cardiovascular risk and vascular damage (reviewed elsewhere49).
The involvement of the RAS in these remodeling features has been investigated in both experimental studies and studies in hypertensive patients. ACE inhibition was effective in correcting vascular structure and decreasing medial collagen deposition in experimental models.72–76 Studies in patients with hypertension treated with ACE inhibitors gave similar beneficial effects in the correction of resistance artery structure. ACE inhibitors proved to be more effective than ß-blockers (atenolol) for both structural77–80 and functional alterations of these resistance arteries.81
The downstream events of ACE in the remodeling of resistance arteries have also been partly elucidated. In SHRs, ACE inhibitors or AT1 receptor antagonists reduced blood pressure and vascular activity of p42/p44 MAPKs (or extracellular signal-regulated kinase 1/2), which are downstream of AT1 receptor–induced Ang II signaling (Figure 2).82 Extracellular signal-regulated kinase 1/2 inhibition improved endothelial function and attenuated Ang II–induced contractility of mesenteric resistance arteries, suggesting that part of the Ang II–induced changes in vascular function are mediated by downstream MAPKs.83
In Ang II–infused mice, an NAD(P)H oxidase inhibitor (apocynin) reduced the blood pressure elevation and prevented structural alterations, endothelial dysfunction, and collagen deposition in the media of small mesenteric arteries, indicating that downstream NAD(P)H oxidase activity is involved in Ang II–induced functional and structural alterations of the vascular wall.84
Finally, in small subcutaneous resistance arteries of mild hypertensive patients, long-term AT1 receptor blockade (1 year) was able to decrease the media-to-lumen ratio. In a parallel group of patients treated with a calcium channel blocker (amlodipine), media-to-lumen ratio continued to increase. AT1 receptor blockade also prevented increases in transforming growth factor-ß and connective tissue growth factor expression and collagen III and IV deposition. All of these parameters continued to increase in amlodipine-treated patients.85 Interestingly, connective tissue growth factor was shown to be downstream of the AT1 receptor (Figure 2) and is considered a novel mediator of Ang II–induced vascular fibrosis.86 Thus, in human resistance arteries, AT1 receptor blockade, but not calcium channel blockade, affected fibrosis, possibly via a connective tissue growth factor–mediated pathway.
The paradigm of beneficial effects of ACE inhibition on vascular remodeling compared with the relative neutral effects of other antihypertensive therapies and whether or not the blood pressure reduction is involved are still the subject of intense investigations. Experimental studies have shown that Ang II caused vascular hypertrophy in part by a nonpressor mechanism. Cotreatment with the vasodilator hydralazine prevented the rise in pressure but not the vascular changes.87 Also, the in vivo gene transfer studies by Morishita et al showed that local expression of ACE induced vascular hypertrophy independent of blood pressure changes.25 Analyses in hypertensive patients, however, showed that the cardiovascular protection induced by antihypertensive drugs was determined by the change in systolic blood pressure, and a minor change in blood pressure (
3 mm Hg) was sufficient to explain the cardiovascular benefits.88,89 This was (partly) challenged by an accompanying analysis of the ASCOT trial,90 which suggested that the amlodipine with or without perindopril treatment regimen had a benefit that extended beyond blood pressure. Although the authors themselves and an editorial89 suggested statistical adjustments as an explanation, it remains possible that effects of the treatment regime on other variables could contribute to the differences in cardiovascular event rates.
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ACE and Atherosclerosis |
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TopAbstractIntroductionVascular Effects of ACE...ACE and Neointimal...ACE and Vascular Remodeling...ACE and AtherosclerosisACE and Aneurysm FormationAngiotensin-Converting Enzyme 2ConclusionReferences |
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Atherosclerosis is a complex, progressive disease of the large systemic arteries and the leading cause of death in the western world. This multifactorial disease is characterized by the accumulation of lipids, cells, and extracellular matrix in the vessel wall. Recent research has shown that inflammation and cytokine pathways are crucial in the development and progression of atherosclerotic lesions. Immune cells are already present in early lesions and cytokine pathways are involved in every stage of the disease. Both animal and human studies have shown that hyperlipidemia results in endothelial activation, which enables infiltration and retention of LDL in the arterial intima. An inflammatory response is initiated in which increased expression of adhesion molecules on the activated endothelium attract leukocytes. Monocytes migrate in the vessel wall, differentiate in macrophages that take up modified LDL, and initiate a tightly regulated network, resulting in a cascade of cytokine secretion. This attracts more inflammatory cells, including T cells. Activated T cells will secrete proinflammatory cytokines and control atherosclerotic plaque inflammatory reactions, also by negative feedback loops, such as secretion of antiinflammatory cytokines by T-regulatory cells.91 There is convincing evidence that Ang II is involved in several important steps of the inflammatory processes during atherosclerosis, such as the increase in vascular permeability and the infiltration of leukocytes. Ang II is also involved in LDL oxidation and uptake, as well as thrombosis (Table 1).
ACE is abundantly expressed in vulnerable lesions and is localized in macrophage foam cells, present in the shoulder region, the endothelial cells of neovessels and spindle-shaped SMCs.92–94 Fukuhara et al also showed ACE expression in foam cells and lymphocytes of human carotid atherosclerotic lesions.95
Hoshida et al measured ACE activity in coronary atherectomies of patients with acute symptoms and stable ischemic heart disease with and without restenosis. Interestingly, ACE activity was significantly increased in the culprit coronary lesions of patients with acute coronary syndrome compared with patients with stable ischemic heart disease.96
Intervention studies in atherosclerotic animal models have shown the atherogenic effect of Ang II and the antiatherogenic effect of ACE inhibitors. Continuous administration of Ang II to ApoE–/– mice significantly increased lesion size.97,98 In atherosclerotic lesions induced by an extravascular device consisting of a tapered collar, Ang II treatment also induced a more vulnerable lesion phenotype, with evidence of intraplaque hemorrhages.99 Interestingly, hypercholesterolemia itself increased plasma angiotensinogen and Ang II concentrations.100 This observation suggests that there may be a positive feedback loop between high cholesterol levels and Ang II, in which high cholesterol levels increases Ang II, and Ang II, in turn, increases lipid uptake.101
The protective actions of ACE inhibitors on atherogenesis have been shown in a number of experimental models. In ApoE–/– mice, fosinopril and captopril inhibited LDL oxidation and reduced atherosclerotic lesion size.102,103 The same protective effects were shown in atherosclerotic minipigs104 and hyperlipidemic rabbits105,106 and monkeys.107 ACE inhibition was also effective in reducing LOX-1 expression in mammary artery biopsies of patients with coronary artery disease.108 Finally, ACE plays an important role in endothelial dysfunction. This is supported by studies in patients with coronary artery disease, showing that ACE inhibitors improved endothelial dysfunction, as measured by flow-mediated dilation of the brachial artery.109,110
The mechanisms by which Ang II can initiate or deteriorate atherosclerosis are partly elucidated. In an elegant study by Cassis et al, using bone marrow transplantation in AT1 subtype a (AT1a) receptor knockout and wild-type mice, it was shown that the AT1a receptor has an important role in the development of Ang II–induced atherosclerosis and aneurysm formation. More specifically, AT1a receptor expressed on bone marrow–derived cells resulted in a modest reduction of Ang II–induced atherosclerosis, whereas the presence of this receptor in the vascular tissue of the recipient was required for the initiation of Ang II–induced atherosclerosis and aneurysms.111 Other studies showed that MCP-1 is an essential inflammatory mediator in Ang II–induced progression of atherosclerosis. Thus, blockade of MCP-1 limited Ang II–induced progression of atherosclerotic lesions in ApoE–/– mice and suppressed the induction of proinflammatory cytokines such as tumor necrosis factor- and IL-6.112 Moreover, this was shown to be dependent on the MCP-1 receptor CCR2 because in CCR2 knockout mice, Ang II–induced cell proliferation, increased wall thickness, and perivascular fibrosis were reduced.113 These studies confirm the important role of MCP-1 as one of the downstream molecules of Ang II–induced activation of the AT1 receptor (Figure 2).
Recently, Kunieda et al suggested another mechanism by which Ang II can accelerate atherosclerosis. In their study, it was shown that Ang II promoted vascular inflammation by inducing premature senescence of SMCs. This pathway was p53/p21 dependent, and p53/p21 inhibition suppressed the induction of proinflammatory cytokines (such as IL-6 and IL-1ß), cellular senescence, and the development of atherosclerosis.114
ACE Inhibition in Patients With Coronary Artery Disease: Clinical Trials
Several large clinical trials have been conducted in which the "antiatherosclerotic" effect of ACE inhibition was studied in patients with cardiovascular disease. Outcomes, however, were variable (see Table 2). In both the HOPE and EUROPE115,116 trials, reduced rates of death from cardiovascular causes were found in patients treated with an ACE inhibitor. Other trials, however, showed no reduction in the incidence of major end points (QUIET,117 PEACE,118 QUASAR,119 PART-2,120 SCAT121). This discrepancy with the overall positive effects of experimental studies in which ACE inhibition proved to be antiatherogenic is similar to what was seen in studies on ACE and remodeling during intimal thickening. Apparently, the complex nature of the disease is not fully represented in the various animal models, and it is likely that therapeutic intervention in a single pathway is not sufficient to reduce the clinical manifestations in patients.
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Recent metaanalyses concluded that the use of ACE inhibitors should be considered in all patients with vascular disease.122–124 However, there were some differences in patient characteristics in the trials used in the metaanalyses, especially with respect to cardiovascular risk. Although HOPE and EUROPE showed that ACE inhibitors lowered cardiovascular morbidity in patients with atherosclerosis and preserved left ventricular function, the PEACE study detected no benefit of ACE inhibition. The PEACE study population had a lower cardiovascular baseline risk (fewer patients with diabetes and high cardiovascular risk), lower arterial blood pressure, and LDL-cholesterol, and patients were treated more frequently with statins and antiplatelet drugs. Thus, as various editorials also pointed out,125,126 what the PEACE study showed was that ACE inhibitors could be beneficial for patients with more risk factors (such as high serum lipids, diabetes mellitus) but may offer modest (to no) extra benefit for patients with low-risk factors or those that are already treated with statins and antiplatelet drugs. From the clinical studies, it can be concluded that aggressive risk factor modification in patients with atherosclerosis is still the primary goal and not all patients may need treatment with ACE inhibitors.
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ACE and Aneurysm Formation |
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TopAbstractIntroductionVascular Effects of ACE...ACE and Neointimal...ACE and Vascular Remodeling...ACE and AtherosclerosisACE and Aneurysm FormationAngiotensin-Converting Enzyme 2ConclusionReferences |
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An aneurysm is defined as a permanent dilation of the arterial wall, which is characterized by outward vessel remodeling, both in vessel dimension and vascular structure. Most aneurysms are asymptomatic and undiagnosed: however, at diameters exceeding 5.5 cm, the risk of rupture increases considerably.127 The underlying problem is weakening of the aortic wall, progressive dilation, and, if left untreated, aortic rupture. Treatment for dilated aneurysms (>5.5 cm) is conventional surgical and endovascular repair and therapeutically much is to be gained for the smaller aneurysms (<5 cm). During aneurysm formation, processes such as proteolysis, inflammation, and oxidant formation are important, and these are also the mechanisms in which ACE and ACE generated regulators are involved.128
ACE is expressed in the aneurysmal vascular wall, both in human disease and animal models. In aneurysmal aortic specimens obtained during operative repair in patients, ACE activity was increased 6-fold. ACE-positive cells (by immunohistochemical staining) were mainly macrophages, both in the media and the intima. Chymase activity was also significantly increased in these specimens and chymase-positive cells were mainly mast cells in the media and adventitia.129 In a rabbit model for aneurysm formation (elastase perfusion), aortic wall ACE protein levels increased during aneurysm growth in time.130
In mice, infusion of Ang II induced aneurysm formation independent of blood pressure changes. This was shown in a hyperlipidemic setting (in ApoE–/– mice) and in wild-type C57BL6 mice, although aneurysm formation was smaller in the wild-type mice.97,131,132 In this model, proteolytic processes are clearly involved because the broad-spectrum matrix metalloproteinase (MMP) inhibitor doxycycline reduced the severity of aneurysm formation.133 Ang II–induced aneurysm formation also displayed characteristic inflammatory features, which fits with the role of Ang II in inflammatory processes as described above. These studies suggest that Ang II, partly because of its inflammatory effects, is an important initiator of aneurysm.
Ang II–induced aneurysm formation was dependent on the presence of the AT1a receptor on bone marrow–derived cells,111 although other studies using AT1 receptor blockers did not show a protective effect on aneurysm formation.134,135 Absence of the MCP receptor CCR2 on bone marrow–derived cells reduced the incidence of Ang II–induced aneurysm formation in ApoE–/– mice.136 Also, a recent study by Thomas et al showed that NAD(P)H oxidase activity is involved in Ang II–induced aneurysm formation. Deletion of p47phox attenuated aneurysm formation and reduced influx of macrophages and MMP-2 activity, again showing the importance of transactivating downstream signaling events of the AT1 receptor.137
ACE inhibition has been shown to be beneficial for both structural and functional properties of aortic aneurysms. In 2 rat models, ACE inhibitors suppressed the development of aortic aneurysms,134,135 whereas in patients with an aneurysm, ACE inhibition was associated with decreased stiffness and greater collagen turnover, which was considered favorable as stiffness is regarded as a risk factor for adverse events.138 In a recent population-based case/control study, ACE inhibition was shown to reduce the risk of rupture of abdominal aortic aneurysms. Other antihypertensive agents, such as ß-blockers, calcium channel blockers, thiazide diuretic, and angiotensin receptor blockers did not have these protective effects.139 Although the numbers of patients that used AT1 receptor blockers in this trial (n=132 patients, 1% of the population) was too small to draw solid conclusions, the surprising lack of effect of AT1 receptor blockers to reduce aneurysm formation was also seen in animal studies.134,135 This would suggest that ACE inhibitors would (1) have a protective effect on aneurysm formation mediated by other AT receptor subtypes, although not all studies confirm this; (2) have influenced the production of other RAS peptides; or (3) have reduced bradykinin degradation. Experimental or clinical studies supporting these mechanisms, however, are lacking.
Another mechanism to consider is the potential of ACE inhibitors to inhibit proteinases involved in extracellular matrix degradation, such as MMPs. The biological mechanism underlying this effect is that ACE inhibitors distinctively bind zinc, which is a cofactor for a number of MMPs. Indeed, several studies have shown that ACE inhibitors specifically protect against rupture of the internal elastica lamina in vivo,104,140 increased collagen type III synthesis in patients with aneurysm (assessed by circulating levels of propeptide of type III procollagen),141 and reduced MMP-2 and MMP-3 gene and protein expression in human SMC cultures in vitro.142 Thus, the capability of ACE inhibitors to directly inhibit MMPs could have an important role in their therapeutic effect during aneurysm formation.
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Angiotensin-Converting Enzyme 2 |
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TopAbstractIntroductionVascular Effects of ACE...ACE and Neointimal...ACE and Vascular Remodeling...ACE and AtherosclerosisACE and Aneurysm FormationAngiotensin-Converting Enzyme 2ConclusionReferences |
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ACE2 is a recently discovered homolog of ACE,143–145 with a different catalytic profile. Data thus far suggest that ACE2 may act as a tissue-specific negative feedback regulator of the activated RAS.146 Ang II serves as a substrate for ACE2 to generate Ang(1–7), and Ang I is an ACE2 substrate to generate Ang(1–9).147 The function of Ang(1–9) is not yet well defined. Ang(1–7) may induce vasodilation and growth arrest (other substrates of ACE2 in Table 1). ACE2 may antagonize the actions of the ACE-Ang II axis, through both RAS-dependent and -independent effects. ACE2 itself may be antagonized by Ang II via a negative feedback loop of Ang II on ACE2 expression and activity.148
ACE2 and Vascular Remodeling
Although ACE2 activity has not yet been determined in the vascular wall, both protein and mRNA are expressed in human coronary arteries and arterioles and the vasa vasorum of most organs.144,149 Recently, expression has also been shown in the large conduit arteries, ie, in the aorta and carotid of SHRs.150 ACE2 localizes preferentially to endothelial cells and arterial SMCs.144,149
As for the role of ACE2 in vascular remodeling, the effect of ACE2 on neointima formation has not yet been studied, but Ang(1–7) infusion after balloon-catheter injury of the rat carotid artery reduced neointima formation.151 This effect was probably mediated by its inhibition of vascular SMC proliferation.152 In hypertensive animal models, ACE2 mRNA and protein were associated with immunoreactive Ang(1–7) in the large conduit arteries of SHRs. Treatment with an AT1 receptor blocker induced a fivefold increase in ACE2 mRNA and was associated with a significant increase in aortic Ang(1–7) protein expression. This effect was associated with a decrease in aortic medial thickness, suggesting that this may be a protective mechanism in the prevention of cardiovascular events during hypertension.150
ACE2 and Atherosclerosis
Studies on the expression and activity of ACE2 in atherosclerosis are limited. Zulli et al showed the expression of ACE2 in endothelial cells, macrophages, and SMCs of aortic atherosclerosis in hypercholesterolemic rabbits.153 No data on ACE2 activity in the lesions were presented. Notably, ACE2 was not expressed in endothelial cells of nondiseased thoracic aorta.
Recently, we have shown the presence of ACE2 mRNA (Figure 3) and its activity in human carotid atherosclerosis. ACE2 mRNA was present in all lesion types (early, advanced stable lesion, and lesions containing a thrombus). ACE2 protein was enzymatically active and lower in the stable advanced atherosclerotic lesions, compared with early lesions and lesions containing a thrombus. This suggests differential regulation of the ACE-ACE2 balance during progression of advanced to ruptured lesions (Sluimer et al154 and SH, JS, MJAPD, JM Gase, A Michaud and P Corvol, unpublished observations, 2007).
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Conclusion |
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TopAbstractIntroductionVascular Effects of ACE...ACE and Neointimal...ACE and Vascular Remodeling...ACE and AtherosclerosisACE and Aneurysm FormationAngiotensin-Converting Enzyme 2ConclusionReferences |
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Since its discovery, the RAS has evolved from a "simple" circulating hormonal system to a multifunctional system in which the traditional vasoactive role of Ang II is complemented with a plethora of other functions, such as oxidant stress and inflammatory and prothrombotic effects. Both experimental and clinical studies have shown the role of ACE and ACE generated proteins in vascular remodeling during restenosis, hypertension, atherosclerosis, and aneurysm formation. In experimental models of restenosis, hypertension, atherosclerosis, and aneurysm formation, ACE inhibition is generally effective in reversing vascular remodeling. Surprisingly, clinical trials, however, have not always confirmed these beneficial effects (see Figure 4). This discrepancy with the overall positive effects of experimental studies in which ACE inhibition proved to affect vascular remodeling is most likely related to the use of animal models. Apparently, the complex nature of the disease is not fully represented in these models, and it is likely that therapeutic intervention in a single pathway is not sufficient to reduce the clinical manifestations in patients. Clearly, more research is needed here, including the development of animal models that represent end-stage human disease.
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For restenosis, ACE inhibition is not effective in reducing adverse events in patients following PTCA, and it is not likely that ACE inhibitors will be a therapeutic modality in restenosis. Several trials using ACE inhibition in patients with atherosclerosis and preserved cardiac function have been conducted; however, not all trials show beneficial effects on prevention of cardiovascular events. This questions the therapeutic potential of ACE inhibitors in these patients. It is thought that ACE inhibitors may be beneficial for patients with more risk factors but offer modest (to no) extra benefit for patients with low-risk factors or those who are already receiving treatment with statins and antiplatelet drugs. For aneurysm formation, there is 1 clinical trial that suggests that ACE inhibition reduces the risk of rupture of abdominal aortic aneurysms; thus, ACE inhibitors could be a therapeutic option; however, a direct effect of ACE inhibitors on MMP inhibition has to be considered as part of the working mechanism, and this needs to be further explored.
The impact of non–ACE-dependent Ang II generation by chymase is likely to be heterogeneous as expression and activity of chymase is highly species and vessel dependent. ACE2 is a recently discovered homologue of ACE, generating active peptide, such as Ang(1–7), and participating in the complex network and feedback mechanisms of the RAS. The role of ACE2 in vascular remodeling has yet to be established; however, ACE2 has been shown to be associated with vascular changes in hypertension and atherosclerosis. It is anticipated that ACE2 is important in the regulatory feedback mechanisms that control the RAS; however, more studies are needed to assess the exact role of ACE2 in various vascular pathologies.
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Acknowledgments |
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We gratefully acknowledge Dr J. M. Gasc and Dr P. Corvol (Collège-de-France, INSERM U36, Paris, France) for contributions to the preliminary data on ACE2 in human atherosclerosis.
Sources of Funding
S.H. and M.J.A.P.D. participate in the European Vascular Genomics Network (http://www.evgn.org), a Network of Excellence supported by the European Community’s Sixth Framework Program for Research Priority 1 (Life Sciences, Genomics, and Biotechnology for Health; contract LSHM-CT-2003-503254).
Disclosures
None.
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Footnotes |
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Original received January 11, 2007; revision received June 19, 2007; accepted July 19, 2007.
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References |
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|
TopAbstractIntroductionVascular Effects of ACE...ACE and Neointimal...ACE and Vascular Remodeling...ACE and AtherosclerosisACE and Aneurysm FormationAngiotensin-Converting Enzyme 2ConclusionReferences |
|---|
1. Hacking WJ, VanBavel E, Spaan JA. Shear stress is not sufficient to control growth of vascular networks: a model study. Am J Physiol. 1996; 270: H364–H375.[Medline] [Order article via Infotrieve]
2. Pasterkamp G, Galis ZS, de Kleijn DP. Expansive arterial remodeling: location, location, location. Arterioscler Thromb Vasc Biol. 2004; 24: 650–657.
3. Baumbach GL, Heistad DD. Remodeling of cerebral arterioles in chronic hypertension. Hypertension. 1989; 13: 968–972.
4. Folkow B. Physiological aspects of primary hypertension. Physiol Rev. 1982; 62: 347–504.
5. Mulvany MJ, Baumbach GL, Aalkjaer C, Heagerty AM, Korsgaard N, Schiffrin EL, Heistad DD. Vascular remodeling. Hypertension. 1996; 28: 505–506.[Medline] [Order article via Infotrieve]
6. Korner PI, Angus JA. Vascular remodeling. Hypertension. 1997; 29: 1065–1066.[Medline] [Order article via Infotrieve]
7. Pasterkamp G, de Kleijn DP, Borst C. Arterial remodeling in atherosclerosis, restenosis and after alteration of blood flow: potential mechanisms and clinical implications. Cardiovasc Res. 2000; 45: 843–852.
8. Ward MR, Pasterkamp G, Yeung AC, Borst C. Arterial remodeling. Mechanisms and clinical implications. Circulation. 2000; 102: 1186–1191.
9. Schiffrin EL. Remodeling of resistance arteries in essential hypertension and effects of antihypertensive treatment. Am J Hypertens. 2004; 17: 1192–1200.[CrossRef][Medline] [Order article via Infotrieve]
10. Dzau VJ. Theodore Cooper Lecture. Tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. Hypertension. 2001; 37: 1047–1052.
11. Ohtsu H, Suzuki H, Nakashima H, Dhobale S, Frank GD, Motley ED, Eguchi S. Angiotensin II signal transduction through small GTP-binding proteins: mechanism and significance in vascular smooth muscle cells. Hypertension. 2006; 48: 534–540.
12. Takai Y, Sasaki T, Matozaki T. Small GTP-binding proteins. Physiol Rev. 2001; 81: 153–208.
13. Yin G, Yan C, Berk BC. Angiotensin II signaling pathways mediated by tyrosine kinases. Int J Biochem Cell Biol. 2003; 35: 780–783.[CrossRef][Medline] [Order article via Infotrieve]
14. Schiffrin EL, Touyz RM. From bedside to bench to bedside: role of renin-angiotensin-aldosterone system in remodeling of resistance arteries in hypertension. Am J Physiol Heart Circ Physiol. 2004; 287: H435–H446.
15. Touyz RM, Schiffrin EL. Reactive oxygen species in vascular biology: implications in hypertension. Histochem Cell Biol. 2004; 122: 339–352.[CrossRef][Medline] [Order article via Infotrieve]
16. Grafe M, Auch-Schwelk W, Zakrzewicz A, Regitz-Zagrosek V, Bartsch P, Graf K, Loebe M, Gaehtgens P, Fleck E. Angiotensin II-induced leukocyte adhesion on human coronary endothelial cells is mediated by E-selectin. Circ Res. 1997; 81: 804–811.
17. Tummala PE, Chen XL, Sundell CL, Laursen JB, Hammes CP, Alexander RW, Harrison DG, Medford RM. Angiotensin II induces vascular cell adhesion molecule-1 expression in rat vasculature: a potential link between the renin-angiotensin system and atherosclerosis. Circulation. 1999; 100: 1223–1229.
18. Alvarez A, Cerda-Nicolas M, Naim Abu Nabah Y, Mata M, Issekutz AC, Panes J, Lobb RR, Sanz MJ. Direct evidence of leukocyte adhesion in arterioles by angiotensin II. Blood. 2004; 104: 402–408.
19. Kranzhofer R, Schmidt J, Pfeiffer CA, Hagl S, Libby P, Kubler W. Angiotensin induces inflammatory activation of human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 1999; 19: 1623–1629.
20. Ruiz-Ortega M, Ruperez M, Lorenzo O, Esteban V, Blanco J, Mezzano S, Egido J. Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney. Kidney Int Suppl. 2002; (82): 12–22.
21. Brasier AR, Jamaluddin M, Han Y, Patterson C, Runge MS. Angiotensin II induces gene transcription through cell-type-dependent effects on the nuclear factor-kappaB (NF-kappaB) transcription factor. Mol Cell Biochem. 2000; 212: 155–169.[CrossRef][Medline] [Order article via Infotrieve]
22. Fleming I. Signaling by the angiotensin-converting enzyme. Circ Res. 2006; 98: 887–896.
23. Rakugi H, Kim DK, Krieger JE, Wang DS, Dzau VJ, Pratt RE. Induction of angiotensin converting enzyme in the neointima after vascular injury. Possible role in restenosis. J Clin Invest. 1994; 93: 339–346.[Medline] [Order article via Infotrieve]
24. Akishita M, Shirakami G, Iwai M, Wu L, Aoki M, Zhang L, Toba K, Horiuchi M. Angiotensin converting enzyme inhibitor restrains inflammation-induced vascular injury in mice. J Hypertens. 2001; 19: 1083–1088.[CrossRef][Medline] [Order article via Infotrieve]
25. Morishita R, Gibbons GH, Ellison KE, Lee W, Zhang L, Yu H, Kaneda Y, Ogihara T, Dzau VJ. Evidence for direct local effect of angiotensin in vascular hypertrophy. In vivo gene transfer of angiotensin converting enzyme. J Clin Invest. 1994; 94: 978–984.[Medline] [Order article via Infotrieve]
26. Morishita R, Gibbons GH, Tomita N, Zhang L, Kaneda Y, Ogihara T, Dzau VJ. Antisense oligodeoxynucleotide inhibition of vascular angiotensin-converting enzyme expression attenuates neointimal formation: evidence for tissue angiotensin-converting enzyme function. Arterioscler Thromb Vasc Biol. 2000; 20: 915–922.
27. Eto H, Biro S, Miyata M, Kaieda H, Obata H, Kihara T, Orihara K, Tei C. Angiotensin II type 1 receptor participates in extracellular matrix production in the late stage of remodeling after vascular injury. Cardiovasc Res. 2003; 59: 200–211.
28. Ohtani K, Egashira K, Ihara Y, Nakano K, Funakoshi K, Zhao G, Sata M, Sunagawa K. Angiotensin II type 1 receptor blockade attenuates in-stent restenosis by inhibiting inflammation and progenitor cells. Hypertension. 2006; 48: 664–670.
29. Parmentier JH, Zhang C, Estes A, Schaefer S, Malik KU. Essential role of PKC-zeta in normal and angiotensin II-accelerated neointimal growth after vascular injury. Am J Physiol Heart Circ Physiol. 2006; 291: H1602–H1613.
30. Powell JS, Clozel JP, Muller RK, Kuhn H, Hefti F, Hosang M, Baumgartner HR. Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. Science. 1989; 245: 186–188.
31. Clozel JP, Hess P, Michael C, Schietinger K, Baumgartner HR. Inhibition of converting enzyme and neointima formation after vascular injury in rabbits and guinea pigs. Hypertension. 1991; 18 (suppl II): II-55–II-59.[Medline] [Order article via Infotrieve]
32. Roux SP, Clozel JP, Kuhn H. Cilazapril inhibits wall thickening of vein bypass graft in the rat. Hypertension. 1991; 18 (suppl II): II-43–I-46.[Medline] [Order article via Infotrieve]
33. Chen R, Iwai M, Wu L, Suzuki J, Min LJ, Shiuchi T, Sugaya T, Liu HW, Cui TX, Horiuchi M. Important role of nitric oxide in the effect of angiotensin-converting enzyme inhibitor imidapril on vascular injury. Hypertension. 2003; 42: 542–547.
34. Barker TA, Massett MP, Korshunov VA, Mohan AM, Kennedy AJ, Berk BC. Angiotensin II type 2 receptor expression after vascular injury: differing effects of angiotensin-converting enzyme inhibition and angiotensin receptor blockade. Hypertension. 2006; 48: 942–949.
35. Kobayashi N, Honda T, Yoshida K, Nakano S, Ohno T, Tsubokou Y, Matsuoka H. Critical role of bradykinin/endothelial NO synthase and oxidative stress-LOX-1 pathway in cardiovascular remodeling under chronic angiotensin-converting enzyme inhibition. Atherosclerosis. 2006; 187: 92–100.[CrossRef][Medline] [Order article via Infotrieve]
36. Hanson SR, Powell JS, Dodson T, Lumsden A, Kelly AB, Anderson JS, Clowes AW, Harker LA. Effects of angiotensin converting enzyme inhibition with cilazapril on intimal hyperplasia in injured arteries and vascular grafts in the baboon. Hypertension. 1991; 18 (suppl II): II-70–II-76.[Medline] [Order article via Infotrieve]
37. Faxon DP. Effect of high dose angiotensin-converting enzyme inhibition on restenosis: final results of the MARCATOR Study, a multicenter, double-blind, placebo-controlled trial of cilazapril. The Multicenter Am Research Trial With Cilazapril After Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MARCATOR) Study Group. J Am Coll Cardiol. 1995; 25: 362–369.[Abstract]
38. Multicenter European Research Trial with Cilazapril after Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MERCATOR) Study Group. Does the new angiotensin converting enzyme inhibitor cilazapril prevent restenosis after percutaneous transluminal coronary angioplasty? Results of the MERCATOR study: a multicenter, randomized, double-blind placebo-controlled trial. Circulation. 1992; 86: 100–110.
39. Schwartz RS, Chronos NA, Virmani R. Preclinical restenosis models and drug-eluting stents: still important, still much to learn. J Am Coll Cardiol. 2004; 44: 1373–1385.
40. Rakugi H, Wang DS, Dzau VJ, Pratt RE. Potential importance of tissue angiotensin-converting enzyme inhibition in preventing neointima formation. Circulation. 1994; 90: 449–455.
41. Hollenberg NK. Implications of species difference for clinical investigation: studies on the renin-angiotensin system. Hypertension. 2000; 35: 150–154.
42. Okunishi H, Miyazaki M, Okamura T, Toda N. Different distribution of two types of angiotensin II-generating enzymes in the aortic wall. Biochem Biophys Res Commun. 1987; 149: 1186–1192.[CrossRef][Medline] [Order article via Infotrieve]
43. Okunishi H, Miyazaki M, Toda N. Evidence for a putatively new angiotensin II-generating enzyme in the vascular wall. J Hypertens. 1984; 2: 277–284.[Medline] [Order article via Infotrieve]
44. Okunishi H, Oka Y, Shiota N, Kawamoto T, Song K, Miyazaki M. Marked species-difference in the vascular angiotensin II-forming pathways: humans versus rodents. Jpn J Pharmacol. 1993; 62: 207–210.[Medline] [Order article via Infotrieve]
45. Jin D, Takai S, Yamada M, Sakaguchi M, Miyazaki M. The functional ratio of chymase and angiotensin converting enzyme in angiotensin I-induced vascular contraction in monkeys, dogs and rats. Jpn J Pharmacol. 2000; 84: 449–454.[CrossRef][Medline] [Order article via Infotrieve]
46. Saris JJ, van Dijk MA, Kroon I, Schalekamp MA, Danser AH. Functional importance of angiotensin-converting enzyme-dependent in situ angiotensin II generation in the human forearm. Hypertension. 2000; 35: 764–768.
47. Peters S, Gotting B, Trummel M, Rust H, Brattstrom A. Valsartan for prevention of restenosis after stenting of type B2/C lesions: the VAL-PREST trial. J Invasive Cardiol. 2001; 13: 93–97.[Medline] [Order article via Infotrieve]
48. Lee RM, Owens GK, Scott-Burden T, Head RJ, Mulvany MJ, Schiffrin EL. Pathophysiology of smooth muscle in hypertension. Can J Physiol Pharmacol. 1995; 73: 574–584.[Medline] [Order article via Infotrieve]
49. Schiffrin EL. Effects of antihypertensive drugs on vascular remodeling: do they predict outcome in response to antihypertensive therapy. Curr Opin Nephrol Hypertens. 2001; 10: 617–624.[CrossRef][Medline] [Order article via Infotrieve]
50. Girerd X, Mourad JJ, Copie X, Moulin C, Acar C, Safar M, Laurent S. Noninvasive detection of an increased vascular mass in untreated hypertensive patients. Am J Hypertens. 1994; 7: 1076–1084.[Medline] [Order article via Infotrieve]
51. Boutouyrie P, Bussy C, Lacolley P, Girerd X, Laloux B, Laurent S. Association between local pulse pressure, mean blood pressure, and large-artery remodeling. Circulation. 1999; 100: 1387–1393.
52. Sasaki R, Yamano S, Yamamoto Y, Minami S, Yamamoto J, Nakashima T, Takaoka M, Hashimoto T. Vascular remodeling of the carotid artery in patients with untreated essential hypertension increases with age. Hypertens Res. 2002; 25: 373–379.[CrossRef][Medline] [Order article via Infotrieve]
53. Frohlich ED, Susic D. Blood pressure, large arteries and atherosclerosis. Adv Cardiol. 2007; 44: 117–124.[Medline] [Order article via Infotrieve]
54. Albaladejo P, Bouaziz H, Duriez M, Gohlke P, Levy BI, Safar ME, Benetos A. Angiotensin converting enzyme inhibition prevents the increase in aortic collagen in rats. Hypertension. 1994; 23: 74–82.
55. Levy BI, Michel JB, Salzmann JL, Azizi M, Poitevin P, Safar M, Camilleri JP. Effects of chronic inhibition of converting enzyme on mechanical and structural properties of arteries in rat renovascular hypertension. Circ Res. 1988; 63: 227–239.
56. Kakar P, Lip GY. Hypertension: endothelial dysfunction, the prothrombotic state and antithrombotic therapy. Expert Rev Cardiovasc Ther. 2007; 5: 441–450.[CrossRef][Medline] [Order article via Infotrieve]
57. Morishita R, Higaki J, Okunishi H, Tanaka T, Ishii K, Nagano M, Mikami H, Ogihara T, Murakami K, Miyazaki M. Changes in gene expression of the renin-angiotensin system in two-kidney, one clip hypertensive rats. J Hypertens. 1991; 9: 187–192.[CrossRef][Medline] [Order article via Infotrieve]
58. Okamura T, Miyazaki M, Inagami T, Toda N. Vascular renin-angiotensin system in two-kidney, one clip hypertensive rats. Hypertension. 1986; 8: 560–565.
59. Miyazaki M, Okunishi H, Okamura T, Toda N. Elevated vascular angiotensin converting enzyme in chronic two-kidney, one clip hypertension in the dog. J Hypertens. 1987; 5: 155–160.[CrossRef][Medline] [Order article via Infotrieve]
60. Nakamura Y, Nakamura K, Matsukura T, Nakamura K. Vascular angiotensin converting enzyme activity in spontaneously hypertensive rats and its inhibition with cilazapril. J Hypertens. 1988; 6: 105–110.[Medline] [Order article via Infotrieve]
61. Jandeleit K, Perich R, Jackson B, Johnston CI. Mesenteric resistance and brain microvascular angiotensin-converting enzyme in the spontaneously hypertensive rat. Clin Exp Pharmacol Physiol. 1992; 19: 348–352.[CrossRef][Medline] [Order article via Infotrieve]
62. Frohlich ED, Sasaki O. Dissociation of changes in cardiovascular mass and performance with angiotensin-converting enzyme inhibitors in Wistar-Kyoto and spontaneously hypertensive rats. J Am Coll Cardiol. 1990; 16: 1492–1499.[Abstract]
63. Roman MJ, Alderman MH, Pickering TG, Pini R, Keating JO, Sealey JE, Devereux RB. Differential effects of angiotensin converting enzyme inhibition and diuretic therapy on reductions in ambulatory blood pressure, left ventricular mass, and vascular hypertrophy. Am J Hypertens. 1998; 11: 387–396.[CrossRef][Medline] [Order article via Infotrieve]
64. Mayet Jamil, Stanton AV, Sinclair A-M, MacKay J, Shahi M, Foale RA, Nicolaides A, Poulter NR, Sever PS, McG. Thom SA, Hughes AD. The effects of antihypertensive therapy on carotid vascular structure in man. Cardiovasc Res. 1995; 30: 147–152.[CrossRef][Medline] [Order article via Infotrieve]
65. Boutouyrie P, Bussy C, Hayoz D, Hengstler J, Dartois N, Laloux B, Brunner H, Laurent S. Local pulse pressure and regression of arterial wall hypertrophy during long-term antihypertensive treatment. Circulation. 2000; 101: 2601–2606.
66. Girerd X, Giannattasio C, Moulin C, Safar M, Mancia G, Laurent S. Regression of radial artery wall hypertrophy and improvement of carotid artery compliance after long-term antihypertensive treatment in elderly patients. J Am Coll Cardiol. 1998; 31: 1064–1073.
67. Armentano RL, Barra JG, Santana DB, Pessana FM, Graf S, Craiem D, Brandani LM, Baglivo HP, Sanchez RA. Smart damping modulation of carotid wall energetics in human hypertension: effects of angiotensin-converting enzyme inhibition. Hypertension. 2006; 47: 384–390.
68. Korsgaard N, Aalkjaer C, Heagerty AM, Izzard AS, Mulvany MJ. Histology of subcutaneous small arteries from patients with essential hypertension. Hypertension. 1993; 22: 523–526.
69. Rizzoni D, Porteri E, Guefi D, Piccoli A, Castellano M, Pasini G, Muiesan ML, Mulvany MJ, Rosei EA. Cellular hypertrophy in subcutaneous small arteries of patients with renovascular hypertension. Hypertension. 2000; 35: 931–935.
70. Intengan HD, Schiffrin EL. Structure and mechanical properties of resistance arteries in hypertension: role of adhesion molecules and extracellular matrix determinants. Hypertension. 2000; 36: 312–318.
71. Park JB, Schiffrin EL. Small artery remodeling is the most prevalent (earliest?) form of target organ damage in mild essential hypertension. J Hypertens. 2001; 19: 921–930.[CrossRef][Medline] [Order article via Infotrieve]
72. Shaw LM, George PR, Oldham AA, Heagerty AM. A comparison of the effect of angiotensin converting enzyme inhibition and angiotensin II receptor antagonism on the structural changes associated with hypertension in rat small arteries. J Hypertens. 1995; 13: 1135–1143.[Medline] [Order article via Infotrieve]
73. Li JS, Schiffrin EL. Effect of calcium channel blockade or angiotensin-converting enzyme inhibition on structure of coronary, renal, and other small arteries in spontaneously hypertensive rats. J Cardiovasc Pharmacol. 1996; 28: 68–74.[CrossRef][Medline] [Order article via Infotrieve]
74. Sharifi AM, Li JS, Endemann D, Schiffrin EL. Effects of enalapril and amlodipine on small-artery structure and composition, and on endothelial dysfunction in spontaneously hypertensive rats. J Hypertens. 1998; 16: 457–466.[CrossRef][Medline] [Order article via Infotrieve]
75. Rizzoni D, Castellano M, Porteri E, Bettoni G, Muiesan ML, Cinelli A, Rosei EA. Effects of low and high doses of fosinopril on the structure and function of resistance arteries. Hypertension. 1995; 26: 118–123.
76. Dohi Y, Criscione L, Pfeiffer K, Luscher TF. Angiotensin blockade or calcium antagonists improve endothelial dysfunction in hypertension: studies in perfused mesenteric resistance arteries. J Cardiovasc Pharmacol. 1994; 24: 372–379.[Medline] [Order article via Infotrieve]
77. Rizzoni D, Muiesan ML, Porteri E, Castellano M, Zulli R, Bettoni G, Salvetti M, Monteduro C, Agabiti-Rosei E. Effects of long-term antihypertensive treatment with lisinopril on resistance arteries in hypertensive patients with left ventricular hypertrophy. J Hypertens. 1997; 15: 197–204.[CrossRef][Medline] [Order article via Infotrieve]
78. Thybo NK, Stephens N, Cooper A, Aalkjaer C, Heagerty AM, Mulvany MJ. Effect of antihypertensive treatment on small arteries of patients with previously untreated essential hypertension. Hypertension. 1995; 25: 474–481.
79. Schiffrin EL, Deng LY. Comparison of effects of angiotensin I-converting enzyme inhibition and beta-blockade for 2 years on function of small arteries from hypertensive patients. Hypertension. 1995; 25: 699–703.
80. Schiffrin EL, Deng LY, Larochelle P. Effects of a beta-blocker or a converting enzyme inhibitor on resistance arteries in essential hypertension. Hypertension. 1994; 23: 83–91.
81. Schiffrin EL, Deng LY, Larochelle P. Progressive improvement in the structure of resistance arteries of hypertensive patients after 2 years of treatment with an angiotensin I-converting enzyme inhibitor. Comparison with effects of a beta-blocker. Am J Hypertens. 1995; 8: 229–236.[CrossRef][Medline] [Order article via Infotrieve]
82. Kim S, Murakami T, Izumi Y, Yano M, Miura K, Yamanaka S, Iwao H. Extracellular signal-regulated kinase and c-Jun NH2-terminal kinase activities are continuously and differentially increased in aorta of hypertensive rats. Biochem Biophys Res Commun. 1997; 236: 199–204.[CrossRef][Medline] [Order article via Infotrieve]
83. Touyz RM, Deschepper C, Park JB, He G, Chen X, Neves MF, Virdis A, Schiffrin EL. Inhibition of mitogen-activated protein/extracellular signal-regulated kinase improves endothelial function and attenuates Ang II-induced contractility of mesenteric resistance arteries from spontaneously hypertensive rats. J Hypertens. 2002; 20: 1127–1134.[CrossRef][Medline] [Order article via Infotrieve]
84. Virdis A, Neves MF, Amiri F, Touyz RM, Schiffrin EL. Role of NAD(P)H oxidase on vascular alterations in angiotensin II-infused mice. J Hypertens. 2004; 22: 535–542.[CrossRef][Medline] [Order article via Infotrieve]
85. Gomez-Garre D, Martin-Ventura JL, Granados R, Sancho T, Torres R, Ruano M, Garcia-Puig J, Egido J. Losartan improves resistance artery lesions and prevents CTGF and TGF-beta production in mild hypertensive patients. Kidney Int. 2006; 69: 1237–1244.[CrossRef][Medline] [Order article via Infotrieve]
86. Ruperez M, Lorenzo O, Blanco-Colio LM, Esteban V, Egido J, Ruiz-Ortega M. Connective tissue growth factor is a mediator of angiotensin II-induced fibrosis. Circulation. 2003; 108: 1499–1505.
87. Griffin SA, Brown WC, MacPherson F, McGrath JC, Wilson VG, Korsgaard N, Mulvany MJ, Lever AF. Angiotensin II causes vascular hypertrophy in part by a non-pressor mechanism. Hypertension. 1991; 17: 626–635.
88. Staessen JA, Wang JG, Thijs L. Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet. 2001; 358: 1305–1315.[CrossRef][Medline] [Order article via Infotrieve]
89. Staessen JA, Birkenhager WH. Evidence that new antihypertensives are superior to older drugs. Lancet. 2005; 366: 869–871.[CrossRef][Medline] [Order article via Infotrieve]
90. Poulter NR, Wedel H, Dahlof B, Sever PS, Beevers DG, Caulfield M, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J, Pocock S. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). Lancet. 2005; 366: 907–913.[CrossRef][Medline] [Order article via Infotrieve]
91. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352: 1685–1695.
92. Ribichini F, Pugno F, Ferrero V, Bussolati G, Feola M, Russo P, Di Mario C, Colombo A, Vassanelli C. Cellular immunostaining of angiotensin-converting enzyme in human coronary atherosclerotic plaques. J Am Coll Cardiol. 2006; 47: 1143–1149.
93. Diet F, Pratt RE, Berry GJ, Momose N, Gibbons GH, Dzau VJ. Increased accumulation of tissue ACE in human atherosclerotic coronary artery disease. Circulation. 1996; 94: 2756–2767.
94. Schieffer B, Schieffer E, Hilfiker-Kleiner D, Hilfiker A, Kovanen PT, Kaartinen M, Nussberger J, Harringer W, Drexler H. Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability. Circulation. 2000; 101: 1372–1378.
95. Fukuhara M, Geary RL, Diz DI, Gallagher PE, Wilson JA, Glazier SS, Dean RH, Ferrario CM. Angiotensin-converting enzyme expression in human carotid artery atherosclerosis. Hypertension. 2000; 35: 353–359.
96. Hoshida S, Kato J, Nishino M, Egami Y, Takeda T, Kawabata M, Tanouchi J, Yamada Y, Kamada T. Increased angiotensin-converting enzyme activity in coronary artery specimens from patients with acute coronary syndrome. Circulation. 2001; 103: 630–633.
97. Daugherty A, Manning MW, Cassis LA. Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. J Clin Invest. 2000; 105: 1605–1612.[Medline] [Order article via Infotrieve]
98. Weiss D, Kools JJ, Taylor WR. Angiotensin II-induced hypertension accelerates the development of atherosclerosis in apoE-deficient mice. Circulation. 2001; 103: 448–454.
99. Cheng C, Tempel D, van Haperen R, van der Baan A, Grosveld F, Daemen MJ, Krams R, de Crom R. Atherosclerotic lesion size and vulnerability are determined by patterns of fluid shear stress. Circulation. 2006; 113: 2744–2753.
100. Daugherty A, Rateri DL, Lu H, Inagami T, Cassis LA. Hypercholesterolemia stimulates angiotensin peptide synthesis and contributes to atherosclerosis through the AT1A receptor. Circulation. 2004; 110: 3849–3857.
101. Keidar S, Heinrich R, Kaplan M, Hayek T, Aviram M. Angiotensin II administration to atherosclerotic mice increases macrophage uptake of oxidized ldl: a possible role for interleukin-6. Arterioscler Thromb Vasc Biol. 2001; 21: 1464–1469.
102. Hayek T, Attias J, Smith J, Breslow JL, Keidar S. Antiatherosclerotic and antioxidative effects of captopril in apolipoprotein E-deficient mice. J Cardiovasc Pharmacol. 1998; 31: 540–544.[CrossRef][Medline] [Order article via Infotrieve]
103. Hayek T, Attias J, Coleman R, Brodsky S, Smith J, Breslow JL, Keidar S. The angiotensin-converting enzyme inhibitor, fosinopril, and the angiotensin II receptor antagonist, losartan, inhibit LDL oxidation and attenuate atherosclerosis independent of lowering blood pressure in apolipoprotein E deficient mice. Cardiovasc Res. 1999; 44: 579–587.
104. Charpiot P, Rolland PH, Friggi A, Piquet P, Scalbert E, Bodard H, Barlatier A, Latrille V, Tranier P, Mercier C. ACE inhibition with perindopril and atherogenesis-induced structural and functional changes in minipig arteries. Arterioscler Thromb. 1993; 13: 1125–1138.
105. Chobanian AV, Haudenschild CC, Nickerson C, Drago R. Antiatherogenic effect of captopril in the Watanabe heritable hyperlipidemic rabbit. Hypertension. 1990; 15: 327–331.
106. Schuh JR, Blehm DJ, Frierdich GE, McMahon EG, Blaine EH. Differential effects of renin-angiotensin system blockade on atherogenesis in cholesterol-fed rabbits. J Clin Invest. 1993; 91: 1453–1458.[Medline] [Order article via Infotrieve]
107. Aberg G, Ferrer P. Effects of captopril on atherosclerosis in cynomolgus monkeys. J Cardiovasc Pharmacol. 1990; 15 (suppl 5): S65–S72.[CrossRef]
108. Morawietz H, Rueckschloss U, Niemann B, Duerrschmidt N, Galle J, Hakim K, Zerkowski HR, Sawamura T, Holtz J. Angiotensin II induces LOX-1, the human endothelial receptor for oxidized low-density lipoprotein. Circulation. 1999; 100: 899–902.
109. Mancini GB, Henry GC, Macaya C, O’Neill BJ, Pucillo AL, Carere RG, Wargovich TJ, Mudra H, Luscher TF, Klibaner MI, Haber HE, Uprichard AC, Pepine CJ, Pitt B. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing ENdothelial Dysfunction) Study. Circulation. 1996; 94: 258–265.
110. Anderson TJ, Elstein E, Haber H, Charbonneau F. Comparative study of ACE inhibition, angiotensin II antagonism, and calcium channel blockade on flow-mediated vasodilation in patients with coronary disease (BANFF study). J Am Coll Cardiol. 2000; 35: 60–66.
111. Cassis LA, Rateri DL, Lu H, Daugherty A. Bone marrow transplantation reveals that recipient AT1a receptors are required to initiate angiotensin II-induced atherosclerosis and aneurysms. Arterioscler Thromb Vasc Biol. 2007; 27: 380–386.
112. Ni W, Kitamoto S, Ishibashi M, Usui M, Inoue S, Hiasa K, Zhao Q, Nishida K, Takeshita A, Egashira K. Monocyte chemoattractant protein-1 is an essential inflammatory mediator in angiotensin II-induced progression of established atherosclerosis in hypercholesterolemic mice. Arterioscler Thromb Vasc Biol. 2004; 24: 534–539.
113. Ishibashi M, Hiasa K, Zhao Q, Inoue S, Ohtani K, Kitamoto S, Tsuchihashi M, Sugaya T, Charo IF, Kura S, Tsuzuki T, Ishibashi T, Takeshita A, Egashira K. Critical role of monocyte chemoattractant protein-1 receptor CCR2 on monocytes in hypertension-induced vascular inflammation and remodeling. Circ Res. 2004; 94: 1203–1210.
114. Kunieda T, Minamino T, Nishi J, Tateno K, Oyama T, Katsuno T, Miyauchi H, Orimo M, Okada S, Takamura M, Nagai T, Kaneko S, Komuro I. Angiotensin II induces premature senescence of vascular smooth muscle cells and accelerates the development of atherosclerosis via a p21-dependent pathway. Circulation. 2006; 114: 953–960.
115. Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003; 362: 782–788.[CrossRef][Medline] [Order article via Infotrieve]
116. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000; 342: 145–153.
117. Pitt B, O’Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H, Bass T, Pepine C, Texter M, Haber H, Uprichard A, Cashin-Hemphill L, Lees RS. The QUinapril Ischemic Event Trial (QUIET): evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol. 2001; 87: 1058–1063.[CrossRef][Medline] [Order article via Infotrieve]
118. Braunwald E, Domanski MJ, Fowler SE, Geller NL, Gersh BJ, Hsia J, Pfeffer MA, Rice MM, Rosenberg YD, Rouleau JL. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004; 351: 2058–2068.
119. Pepine CJ, Rouleau JL, Annis K, Ducharme A, Ma P, Lenis J, Davies R, Thadani U, Chaitman B, Haber HE, Freedman SB, Pressler ML, Pitt B. Effects of angiotensin-converting enzyme inhibition on transient ischemia: the Quinapril Anti-Ischemia and Symptoms of Angina Reduction (QUASAR) trial. J Am Coll Cardiol. 2003; 42: 2049–2059.
120. MacMahon S, Sharpe N, Gamble G, Clague A, Mhurchu CN, Clark T, Hart H, Scott J, White H. Randomized, placebo-controlled trial of the angiotensin-converting enzyme inhibitor, ramipril, in patients with coronary or other occlusive arterial disease. PART-2 Collaborative Research Group. Prevention of Atherosclerosis with Ramipril. J Am Coll Cardiol. 2000; 36: 438–443.
121. Teo KK, Burton JR, Buller CE, Plante S, Catellier D, Tymchak W, Dzavik V, Taylor D, Yokoyama S, Montague TJ. Long-term effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis: The Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT). Circulation. 2000; 102: 1748–1754.
122. Danchin N, Cucherat M, Thuillez C, Durand E, Kadri Z, Steg PG. Angiotensin-converting enzyme inhibitors in patients with coronary artery disease and absence of heart failure or left ventricular systolic dysfunction: an overview of long-term randomized controlled trials. Arch Intern Med. 2006; 166: 787–796.
123. Dagenais GR, Pogue J, Fox K, Simoons ML, Yusuf S. Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials. Lancet. 2006; 368: 581–588.[CrossRef][Medline] [Order article via Infotrieve]
124. Al-Mallah MH, Tleyjeh IM, Abdel-Latif AA, Weaver WD. Angiotensin-converting enzyme inhibitors in coronary artery disease and preserved left ventricular systolic function: a systematic review and meta-analysis of randomized controlled trials. J Am Coll Cardiol. 2006; 47: 1576–1583.
125. Remuzzi G, Ruggenenti P. Overview of randomised trials of ACE inhibitors. Lancet. 2006; 368: 555–556.[CrossRef][Medline] [Order article via Infotrieve]
126. Shah AD, Arora RR. Do all patients with coronary artery disease benefit from angiotensin converting enzyme inhibitors. J Cardiovasc Pharmacol Ther. 2005; 10: 281–283.
127. Shimizu K, Mitchell RN, Libby P. Inflammation and cellular immune responses in abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol. 2006; 26: 987–994.
128. Golledge J, Muller J, Daugherty A, Norman P. Abdominal aortic aneurysm: pathogenesis and implications for management. Arterioscler Thromb Vasc Biol. 2006; 26: 2605–2613.
129. Nishimoto M, Takai S, Fukumoto H, Tsunemi K, Yuda A, Sawada Y, Yamada M, Jin D, Sakaguchi M, Nishimoto Y, Sasaki S, Miyazaki M. Increased local angiotensin II formation in aneurysmal aorta. Life Sci. 2002; 71: 2195–2205.[CrossRef][Medline] [Order article via Infotrieve]
130. Eagleton MJ, Cho B, Lynch E, Roelofs K, Woodrum D, Stanley JC, Upchurch GR Jr. Alterations in angiotensin converting enzyme during rodent aortic aneurysm formation. J Surg Res. 2006; 132: 69–73.[CrossRef][Medline] [Order article via Infotrieve]
131. Deng GG, Martin-McNulty B, Sukovich DA, Freay A, Halks-Miller M, Thinnes T, Loskutoff DJ, Carmeliet P, Dole WP, Wang YX. Urokinase-type plasminogen activator plays a critical role in angiotensin II-induced abdominal aortic aneurysm. Circ Res. 2003; 92: 510–517.
132. Daugherty A, Cassis LA. Mouse models of abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol. 2004; 24: 429–434.
133. Manning MW, Cassis LA, Daugherty A. Differential effects of doxycycline, a broad-spectrum matrix metalloproteinase inhibitor, on angiotensin II-induced atherosclerosis and abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol. 2003; 23: 483–488.
134. Liao S, Miralles M, Kelley BJ, Curci JA, Borhani M, Thompson RW. Suppression of experimental abdominal aortic aneurysms in the rat by treatment with angiotensin-converting enzyme inhibitors. J Vasc Surg. 2001; 33: 1057–1064.[CrossRef][Medline] [Order article via Infotrieve]
135. Nagashima H, Uto K, Sakomura Y, Aoka Y, Sakuta A, Aomi S, Hagiwara N, Kawana M, Kasanuki H. An angiotensin-converting enzyme inhibitor, not an angiotensin II type-1 receptor blocker, prevents beta-aminopropionitrile monofumarate-induced aortic dissection in rats. J Vasc Surg. 2002; 36: 818–823.[Medline] [Order article via Infotrieve]
136. Ishibashi M, Egashira K, Zhao Q, Hiasa K, Ohtani K, Ihara Y, Charo IF, Kura S, Tsuzuki T, Takeshita A, Sunagawa K. Bone marrow-derived monocyte chemoattractant protein-1 receptor CCR2 is critical in angiotensin II-induced acceleration of atherosclerosis and aneurysm formation in hypercholesterolemic mice. Arterioscler Thromb Vasc Biol. 2004; 24: e174–e178.
137. Thomas M, Gavrila D, McCormick ML, Miller FJ Jr, Daugherty A, Cassis LA, Dellsperger KC, Weintraub NL. Deletion of p47phox attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient mice. Circulation. 2006; 114: 404–413.
138. Wilmink AB, Vardulaki KA, Hubbard CS, Day NE, Ashton HA, Scott AP, Quick CR. Are antihypertensive drugs associated with abdominal aortic aneurysms. J Vasc Surg. 2002; 36: 751–757.[Medline] [Order article via Infotrieve]
139. Hackam DG, Thiruchelvam D, Redelmeier DA. Angiotensin-converting enzyme inhibitors and aortic rupture: a population-based case-control study. Lancet. 2006; 368: 659–665.[CrossRef][Medline] [Order article via Infotrieve]
140. Huang W, Alhenc Gelas F, Osborne-Pellegrin MJ. Protection of the arterial internal elastic lamina by inhibition of the renin-angiotensin system in the rat. Circ Res. 1998; 82: 879–890.
141. Claridge MW, Hobbs SD, Quick CR, Day NE, Bradbury AW, Wilmink AB. ACE inhibitors increase type III collagen synthesis: a potential explanation for reduction in acute vascular events by ACE inhibitors. Eur J Vasc Endovasc Surg. 2004; 28: 67–70.[CrossRef][Medline] [Order article via Infotrieve]
142. Ahimastos AA, Natoli AK, Lawler A, Blombery PA, Kingwell BA. Ramipril reduces large-artery stiffness in peripheral arterial disease and promotes elastogenic remodeling in cell culture. Hypertension. 2005; 45: 1194–1199.
143. Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000; 275: 33238–33243.
144. Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000; 87: e1–e9.[Medline] [Order article via Infotrieve]
145. Hamming I, Cooper ME, Haagmans BL, Hooper NM, Korstanje R, Osterhaus AD, Timens W, Turner AJ, Navis G, van Goor H. The emerging role of ACE2 in physiology and disease. J Pathol. 2007; 212: 1–11.[CrossRef][Medline] [Order article via Infotrieve]
146. Turner AJ, Hooper NM. The angiotensin-converting enzyme gene family: genomics and pharmacology. Trends Pharmacol Sci. 2002; 23: 177–183.[CrossRef][Medline] [Order article via Infotrieve]
147. Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J, Godbout K, Parsons T, Baronas E, Hsieh F, Acton S, Patane M, Nichols A, Tummino P. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem. 2002; 277: 14838–14843.
148. Ferrario CM, Jessup J, Chappell MC, Averill DB, Brosnihan KB, Tallant EA, Diz DI, Gallagher PE. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005; 111: 2605–2610.
149. Hamming I, Timens W, Bulthuis M, Lely A, Navis G, Van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004; 203: 631–637.[CrossRef][Medline] [Order article via Infotrieve]
150. Igase M, Strawn WB, Gallagher PE, Geary RL, Ferrario CM. Angiotensin II AT1 receptors regulate ACE2 and angiotensin-(1-7) expression in the aorta of spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol. 2005; 289: H1013–H1019.
151. Strawn WB, Ferrario CM, Tallant EA. Angiotensin-(1-7) reduces smooth muscle growth after vascular injury. Hypertension. 1999; 33: 207–211.
152. Freeman EJ, Chisolm GM, Ferrario CM, Tallant EA. Angiotensin-(1-7) inhibits vascular smooth muscle cell growth. Hypertension. 1996; 28: 104–108.
153. Zulli A, Burrell LM, Widdop RE, Black MJ, Buxton BF, Hare DL. Immunolocalization of ACE2 and AT2 receptors in rabbit atherosclerotic plaques. J Histochem Cytochem. 2006; 54: 147–150.
154. Sluimer J, Hamming I, Gasc J, Van Goor H, van den Akker L, Corvol P, Daemen M, Bijnens A. A new ACE on the table: ACE2 expression in human atherosclerosis. J Vasc Res. 2005; 42 (suppl 2): II/13 Abstract.
155. Ruiz-Ortega M, Ruperez M, Esteban V, Rodriguez-Vita J, Sanchez-Lopez E, Carvajal G, Egido J. Angiotensin II: a key factor in the inflammatory and fibrotic response in kidney diseases. Nephrol Dial Transplant. 2006; 21: 16–20.
156. Moreau ME, Garbacki N, Molinaro G, Brown NJ, Marceau F, Adam A. The kallikrein-kinin system: current and future pharmacological targets. J Pharmacol Sci. 2005; 99: 6–38.[CrossRef][Medline] [Order article via Infotrieve]
157. Rajagopalan S, Laursen JB, Borthayre A, Kurz S, Keiser J, Haleen S, Giaid A, Harrison DG. Role for endothelin-1 in angiotensin II-mediated hypertension. Hypertension. 1997; 30: 29–34.
158. Wang HD, Xu S, Johns DG, Du Y, Quinn MT, Cayatte AJ, Cohen RA. Role of NADPH oxidase in the vascular hypertrophic and oxidative stress response to angiotensin II in mice. Circ Res. 2001; 88: 947–953.
159. Lassegue B, Sorescu D, Szocs K, Yin Q, Akers M, Zhang Y, Grant SL, Lambeth JD, Griendling KK. Novel gp91 (phox) homologues in vascular smooth muscle cells: nox1 mediates angiotensin II-induced superoxide formation and redox-sensitive signaling pathways. Circ Res. 2001; 88: 888–894.
160. Daemen MJ, Lombardi DM, Bosman FT, Schwartz SM. Angiotensin II induces smooth muscle cell proliferation in the normal and injured rat arterial wall. Circ Res. 1991; 68: 450–456.
161. deBlois D, Schwartz SM, van Kleef EM, Su JE, Griffin KA, Bidani AK, Daemen MJAP, Lombardi DM. Chronic alpha1-adrenoreceptor stimulation increases DNA synthesis in rat arterial wall. Modulation of responsiveness after vascular injury. Arterioscler Thromb Vasc Biol. 1996; 16: 1122–1129.
162. Pollman MJ, Yamada T, Horiuchi M, Gibbons GH. Vasoactive substances regulate vascular smooth muscle cell apoptosis. Counteracting influences of nitric oxide and angiotensin II. Circ Res. 1996; 79: 748–756.
163. Bell L, Madri JA. Influence of the angiotensin system on endothelial and smooth muscle cell migration. Am J Pathol. 1990; 137: 7–12.[Abstract]
164. Castoldi G, Di Gioia CR, Pieruzzi F, D’Orlando C, Van De Greef WM, Busca G, Sperti G, Stella A. ANG II increases TIMP-1 expression in rat aortic smooth muscle cells in vivo. Am J Physiol Heart Circ Physiol. 2003; 284: H635–H643.
165. Stanley AG, Patel H, Knight AL, Williams B. Mechanical strain-induced human vascular matrix synthesis: the role of angiotensin II. J Renin Angiotensin Aldosterone Syst. 2000; 1: 32–35.
166. Tamarat R, Silvestre JS, Durie M, Levy BI. Angiotensin II angiogenic effect in vivo involves vascular endothelial growth factor- and inflammation-related pathways. Lab Invest. 2002; 82: 747–756.[Medline] [Order article via Infotrieve]
167. Victorino GP, Newton CR, Curran B. Effect of angiotensin II on microvascular permeability. J Surg Res. 2002; 104: 77–81.[CrossRef][Medline] [Order article via Infotrieve]
168. Skidgel RA, Stanisavljevic S, Erdos EG. Kinin- and angiotensin-converting enzyme (ACE) inhibitor-mediated nitric oxide production in endothelial cells. Biol Chem. 2006; 387: 159–165.[CrossRef][Medline] [Order article via Infotrieve]
169. Groves P, Kurz S, Just H, Drexler H. Role of endogenous bradykinin in human coronary vasomotor control. Circulation. 1995; 92: 3424–3430.
170. Wollert KC, Drexler H. The kallikrein-kinin system in post-myocardial infarction cardiac remodeling. Am J Cardiol. 1997; 80: 158A–161A.[CrossRef][Medline] [Order article via Infotrieve]
171. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991; 43: 109–142.[Medline] [Order article via Infotrieve]
172. Rasoul S, Carretero OA, Peng H, Cavasin MA, Zhuo J, Sanchez-Mendoza A, Brigstock DR, Rhaleb NE. Antifibrotic effect of Ac-SDKP and angiotensin-converting enzyme inhibition in hypertension. J Hypertens. 2004; 22: 593–603.[CrossRef][Medline] [Order article via Infotrieve]
173. Wang D, Carretero OA, Yang XY, Rhaleb NE, Liu YH, Liao TD, Yang XP. N-acetyl-seryl-aspartyl-lysyl-proline stimulates angiogenesis in vitro and in vivo. Am J Physiol Heart Circ Physiol. 2004; 287: H2099–H2105.
174. Sampaio WO, Nascimento AA, Santos RA. Systemic and regional hemodynamic effects of angiotensin-(1-7) in rats. Am J Physiol Heart Circ Physiol. 2003; 284: H1985–H1994.
175. le Tran Y, Forster C. Angiotensin-(1-7) and the rat aorta: modulation by the endothelium. J Cardiovasc Pharmacol. 1997; 30: 676–682.[CrossRef][Medline] [Order article via Infotrieve]
176. Keidar S, Kaplan M, Gamliel-Lazarovich A. ACE2 of the heart: From angiotensin I to angiotensin (1-7). Cardiovasc Res. 2007; 73: 463–469.
177. Ueda S, Masumori-Maemoto S, Ashino K, Nagahara T, Gotoh E, Umemura S, Ishii M. Angiotensin-(1-7) attenuates vasoconstriction evoked by angiotensin II but not by noradrenaline in man. Hypertension. 2000; 35: 998–1001.
178. McLean PG, Perretti M, Ahluwalia A. Kinin B (1) receptors and the cardiovascular system: regulation of expression and function. Cardiovasc Res. 2000; 48: 194–210.
179. Kleinz MJ, Davenport AP. Emerging roles of apelin in biology and medicine. Pharmacol Ther. 2005; 107: 198–211.[CrossRef][Medline] [Order article via Infotrieve]
180. Danilczyk U, Penninger JM. Angiotensin-converting enzyme II in the heart and the kidney. Circ Res. 2006; 98: 463–471.
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