Journal of Human (2002) 16, S34–S41  2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh

The potential role of AT1-receptor blockade in the prevention and reversal of

V Papademetriou Hypertension and Cardiovascular Research Clinic, VA Medical Center, Georgetown University, Washington DC, USA

The renin-angiotensin system may contribute to the animal experiments, treatment with ACE inhibitors or

development and progression of atherosclerosis both angiotensin AT1-receptor blockers has been shown to by increasing and by direct effects on have anti-atherogenic effects. Studies with candesartan all phases of the atherogenic process. Genetic determi- have shown that this agent produces a dose-dependent nants of renin-angiotensin system activation, notably reduction in uptake of oxidised LDL by mouse macro- the DD genotype of angiotensin converting enzyme phages in vitro, and reduces accumulation (ACE), are associated with an increased risk of cardio- and atherosclerosis development in the aorta of Watan- vascular events, as is increased plasma renin activity. abe rabbits. These effects were independent of changes In addition, angiotensin II has been shown to increase in blood pressure. Such findings suggest that

the uptake and oxidation of low density AT1-receptor blockers may be beneficial in reducing (LDL) by and endothelial cells. Angioten- mortality and morbidity resulting from atherosclerotic sin II also stimulates the production of interleukin 6 and disease, and are consistent with the findings from large ␬ activates the pro-inflammatory factor nuclear factor B, outcome trials with ACE inhibitors in patients at risk of leading to expression of adhesion molecules and cardiovascular events. recruitment of monocytes and macrophages, and Journal of Human Hypertension (2002) 16, S34–S41. increases the production of pro-coagulatory factors. In doi:10.1038/sj.jhh.1001437

Keywords: AT1-receptor blockers; atherosclerosis; candesartan; irbesartan; losartan; renin-angiotensin system

Introduction valuable therapeutic target for the prevention of atherosclerosis. Atherosclerosis is a complex process that may pro- gress for several decades before becoming manifest as a cardiovascular event such as myocardial infarc- Involvement of the renin-angiotensin tion. The process begins with endothelial dysfunc- system in atherogenesis tion, which leads to monocyte activation and migration into the subintimal layer, lipid oxidation There is good evidence from epidemiological, lab- and uptake, accumulation, and the forma- oratory and clinical studies that the renin-angioten- tion of fatty streaks, culminating in the development sin system contributes to atherosclerosis not only by of an atherosclerotic plaque.1,2 Thrombus formation increasing blood pressure, but also through multiple at the site of ruptured plaques, or intermittent direct effects on the arterial wall. at intact plaques, leads ultimately to car- diovascular events. The risk of cardiovascular Effects on blood pressure events resulting from atherosclerosis is influenced

by a number of well established risk factors, includ- Angiotensin II, through its action on AT1-receptors, ing hypertension,3 hypercholesterolaemia,4 dia- is a potent vasoconstrictor,7 and can also increase betes5 and smoking.6 In addition, there is increasing blood pressure indirectly through activation of the evidence that the renin-angiotensin system plays an sympathetic nervous system.8 It is well established, important role in the development and progression from studies such as the Framingham Study3 and of atherosclerosis, making this system a potentially the Multiple Risk Factors Intervention Trial (MRFIT),9 that there is a continuous relationship between elevated blood pressure and the risk of car- diovascular events, and that lowering blood pres- 10 Correspondence: Professor V Papademetriou, VA Medical Center, sure reduces the risk of such events. It appears, 50 Irving St NW, Washington DC 20422, USA however, that a certain minimum level of blood Role of angiotensin II in atherosclerosis V Papademetriou S35 pressure is necessary for atherosclerosis to develop. myocardial infarction associated with the DD geno- Atherosclerosis only occurs in high-pressure type was 2.11 (95% confidence interval 1.23–3.62, vascular beds. It does not, for example, develop in P = 0.007).13 Similarly, in a study in Japan, the DD the pulmonary circulation except in the presence of genotype occurred more commonly in patients with , and is not seen in coronary disease than in healthy individuals , except in venous grafts in the arterial system. (58% vs 42%, respectively), and the relative risk of Furthermore, in patients with aortic coarctation, myocardial infarction associated with the DD atherosclerosis is confined to the proximal segment, genotype was 2.81 (1.79–4.41, P Ͻ 0.001);14,15 in where pressure is high, and does not occur distal to other Asian populations, the relative risk was 1.88 the site of coarctation. The level of blood pressure (1.43–2.48, P Ͻ 0.001).12 In a large case-control required for atherosclerosis to develop has not been study, involving 2267 male German caucasians, established. In the Hypertension Optimal Treatment there was a strong association between the presence (HOT) Study, the lowest incidence of major cardio- of the DD genotype and the risk of coronary artery vascular events (non-fatal stroke or myocardial disease, particularly in individuals without other infarction, and cardiovascular death) was seen at risk factors.16 mean systolic and diastolic blood pressures of 138.5 mm Hg and 82.6 mm Hg, respectively, and the Plasma renin activity: There is a well established lowest risk of cardiovascular death at pressures of relationship between elevated plasma renin activity 138.8 mm Hg and 86.5 mm Hg, respectively.11 and the risk of . In one study, for example, plasma renin activity was determined before starting antihypertensive treatment in 1717 Evidence for direct effects of the renin-angiotensin patients with mild-to-moderate hypertension.17 Dur- system on atherogenesis ing the subsequent 8 years of antihypertensive ther- Several lines of evidence suggest that the renin- apy, a total of 27 myocardial infarctions occurred in angiotensin system directly influences the risk of these patients. After adjustment for age, gender and atherogenesis (Table 1). race, the incidence of myocardial infarction in patients with high plasma renin activity at baseline Genetic determinants of renin-angiotensin system was 14.7/1000 person-years, compared with activation: Variations in the angiotensin con- 5.6/1000 person-years among those with normal verting enzyme (ACE) genotype have been shown to renin levels, and 2.8/1000 person-years in those be associated with an increased risk of cardiovascu- with low plasma renin activity. Similarly, all-cause lar events. The most extensively studied of these mortality was markedly higher among patients with variations is ACE I/D polymorphism.12 This is high plasma renin activity than in those with normal characterised by the presence (I) or absence (D) of a or low renin activity (9.3, 5.3 and 3.9/1000 person- 287 base pair sequence within intron 16 of the ACE years, respectively). Multivariate analysis showed gene, and the D allele is associated with increased that elevated plasma renin activity was a powerful ACE activity; in most populations, the DD genotype independent risk factor for myocardial infarction, is associated with plasma ACE activity approxi- but the risk was increased still further when other mately 20 times higher than that observed in indi- risk factors were present (Figure 1). viduals with the DI genotype, and 40 times higher than in those with the II genotype.12 Studies in Anti-ischaemic effects: Large outcome studies with countries with genetically homogeneous popu- ACE inhibitors have consistently shown that these lations have shown that the DD genotype is associa- agents reduce cardiovascular mortality and mor- ted with an approximately two to three-fold increase bidity in high-risk patients.18–23 In addition, how- in the risk of cardiovascular events. For example, in ever, these studies have shown that ACE inhibitor a study in Turkey involving patients with previous therapy reduces the incidence of recurrent myocar- myocardial infarction, the relative risk of dial infarction, by approximately 7–9% each year (Figure 2). This finding suggests that ACE inhibitors have anti-ischaemic effects, probably related to Table 1 Evidence for involvement of the renin angiotensin system in atherosclerosis stabilisation of atherosclerotic plaques.

• Association of DD ACE genotype with risk of ischaemic Presence of ACE in atherosclerotic plaques: Recent events studies show that ACE is abundant at sites of athero- • Relationship between plasma renin activity and risk of sclerosis. In one study, for example, endarterectomy ischaemic events specimens were obtained from 24 patients with sev- • Anti-ischaemic effects of renin-angiotensin system ere occlusive carotid artery disease, and ACE mRNA blockade and protein were localised by in situ hybridisation • Presence of ACE in atherosclerotic plaques and immunohistochemistry.24 ACE was localised in • Multiple atherogenic actions of angiotensin II in the intima, and the degree of staining increased as experimental models lesions became more complex; the underlying media and smooth muscle were largely devoid of ACE. In

Journal of Human Hypertension Role of angiotensin II in atherosclerosis V Papademetriou S36 Atherogenic effects of angiotensin II Experimental data show that angiotensin II has mul- tiple effects in the vessel wall that can contribute to the development and progression of atherosclerosis, including effects on lipid metabolism, inflam- mation, smooth muscle cell proliferation, and coagulation (Table 2).25

Effects on lipid metabolism: Angiotensin II has been shown to enhance the oxidation and uptake of low density lipoprotein (LDL) by macrophages and endothelial cells.26,27 Some of this activity may be mediated via the LOX-1 receptor, a recently dis- covered receptor for oxidised LDL that is present in vascular , and the expression of which is increased in atherosclerotic lesions.28 Recent studies have shown that expression of this receptor is increased by angiotensin II and, conversely, expression of the AT1-receptor is up-regulated by oxidised LDL.29

Figure 1 Risk of myocardial infarction according to plasma renin Effects on inflammation: Expression of interleukin activity at baseline in 1717 patients with mild-to-moderate hyper- (IL)-6 and other cytokines in vascular smooth mus- 17 tension treated for 8 years. cle leads to recruitment of monocytes, which secrete enzymes such as collagenase and gelatinase, leading to plaque destabilisation. Inflammation thus plays an important role in destabilisation of the athero- sclerotic plaque and the development of vascular events. Angiotensin II has been shown to stimulate IL-6 expression in vascular smooth muscle and human coronary atherosclerotic plaques.30,31 This effect is mediated via activation of nuclear factor ␬ (NF)- B, a pro-inflammatory factor that is required for expression of cytokines such as IL-6.32,33 Acti- ␬ vation of NF- B also increases the production of various adhesion molecules that are involved in the recruitment of monocytes, such as vascular adhesion molecule (VCAM)-1 and intracellular adhesion molecule (ICAM)-1. This effect can be blocked by angiotensin AT1-receptor antagonists. In one study, for example, hypertensive transgenic rats were treated for 12 days with losartan, 10 mg/kg/24 h, hydralazine, 3 mg/kg/24 h, or saline.34 Both active treatments significantly reduced endothelial cell injury in the thoracic aorta, but only losartan reduced the number of activated Figure 2 Annual reductions in risk of recurrent myocardial monocytes in the circulation and monocyte infarction in long-term outcome trials with ACE inhibitors. AIRE: adhesion to the endothelium. These effects of Acute Infarction Ramipril Efficacy Study;22 SAVE: Survival And Ventricular Enlargement Study;20 SOLVD Pre-, SOLVD Rx: Stud- ies of Left Ventricular Dysfunction Prevention and Treatment trials;18,19 TRACE: Trandolapril Cardiac Evaluation Study.21 Table 2 Vascular mechanisms by which the renin-angiotensin system may contribute to atherosclerosis2

• Vasoconstriction and increased blood pressure less complicated lesions, ACE could be visualised • in clusters and on the luminal side of Effects on LDL oxidation • the endothelium. The shoulder regions of athero- Effects on inflammation sclerotic plaques, which are a frequent site of plaque • Effects on coagulation rupture, showed extensive staining for ACE activity • Effects on vascular remodelling that was associated with macrophage foam cells • Effects on angiogenesis and lymphocytes.

Journal of Human Hypertension Role of angiotensin II in atherosclerosis V Papademetriou S37 AT1-receptor blockade were independent of changes Diet-induced atherosclerotic lesions are similar to in blood pressure. those seen in the human coronary circulation,39 and the development of these lesions follows a similar Effects on smooth muscle migration and prolifer- pattern to that seen in humans, progressing from ation: Angiotensin II induces the expression of foam cell accumulation and fatty streak forma- autocrine growth factors such as basic fibroblast- tion.40,41 In the study by Strawn et al,38 male cyno- derived growth factor, -derived growth factor molgus monkeys were fed an atherogenic diet con- and transforming growth factor-␤1, thereby stimulat- taining 0.067 mg cholesterol/kJ for 20 weeks. After ing vascular smooth muscle proliferation.35,36 In 12 weeks, the animals were randomised according addition, angiotensin II contributes to vascular to their plasma cholesterol concentrations to receive remodelling by modulating smooth muscle losartan, 180 mg/day, or vehicle via osmotic mini- migration and inhibiting smooth muscle apoptosis pumps for 6 weeks. Two weeks after the end of this (programmed cell death) in vascular tissue.25 treatment, the animals were killed and their aortas and other vessels removed for histological and Effects on coagulation factors: Angiotensin II shifts immunohistochemical examination. the haemostatic balance towards an increased risk At the end of the study, there were no significant of thrombosis by increasing concentrations of plas- differences in blood pressure, total cholesterol con- minogen activator inhibitor (PAI-I) and reducing centrations, or plasma lipoprotein distribution concentrations of tissue plasminogen activator between actively-treated animals and controls. How- (tPA). This effect can be blocked by ACE inhibitors ever, monocyte CD11b expression in whole blood 37 or AT1-receptor antagonists. and isolated monocytes was significantly reduced by In summary, angiotensin II has a number of AT1-receptor blockade, indicating reduced mono- atherogenic effects (Figure 3), which cause endo- cyte activation and adhesion. AT1-receptor blockade thelial dysfunction, monocyte adhesion and release also produced a significant increase in the lag time of inflammatory factors, foam cell formation, smooth required for LDL oxidation in vitro, indicating muscle hypertrophy, and an increased risk of throm- decreased LDL uptake and oxidation. Furthermore, bosis. Angiotensin II thus affects all phases of the fatty streak formation in the aorta, the left anterior atherosclerotic process. descending coronary artery, the left circumflex artery and the right coronary artery was reduced by Anti-atherogenic effects of renin- approximately 50%, providing direct evidence that AT1-receptor blockade prevented the development angiotensin system blockade of atherosclerosis in this model. This reduction in A number of studies have investigated the impact fatty streak formation was associated with a signifi- of AT1-receptor blockers or ACE inhibitors on the cant decrease in the cholesterol content of the development and progression of atherosclerosis in carotid . animal models. A recent study, for example, has In a second study, Watanabe heritable hyperlipid- investigated the effects of AT1-receptor blockade in aemic rabbits were treated with the ACE inhibitor cynomolgus monkeys.38 This species offers a num- trandolapril, 0.25 mg/kg/48 h, between the ages of 3 ber of advantages as a model of atherosclerosis. and 12 months.42 The development of atherosclerosis

Figure 3 Atherogenic effects of angiotensin II.

Journal of Human Hypertension Role of angiotensin II in atherosclerosis V Papademetriou S38 in the aorta was significantly reduced in trandolap- ril-treated animals, compared with controls: 35% of the total aortic intimal surface was affected by atherosclerosis, compared with 56% in control ani- mals. Similar reductions were seen in the ascending aorta (82% vs 95%), the descending aorta (22% vs 54%) and the abdominal aorta (24% vs 39%). The cholesterol content in the descending aortic arch was significantly lower in trandolapril-treated ani- mals than in controls, and atherosclerotic plaques from these animals appeared to contain fewer foam cells and more connective tissue than those from control animals. In this study, however, ACE inhibi- tor therapy produced a significant reduction in blood pressure, compared with the control group, and hence it is not possible to distinguish between the anti-atherogenic effects of blood pressure reduction and potential direct effects of ACE inhi- bition. This issue was addressed in a subsequent study, Figure 4 Uptake of oxidised LDL (oxLDL) by murine macro- in which Watanabe rabbits were treated with the phages incubated for 6 h with angiotensin II or candesartan.45 AT1-receptor blocker irbesartan at doses of Reproduced with permission from Papademetriou V et al. Preven- 30 mg/kg/day and 75 mg/kg/day.43 The lower dose tion of atherosclerosis by specificAT1-receptor blockade with of irbesartan had no significant effect on blood candesartan cilexetil. JRAAS 2001; 2 (Suppl 1): S77–S80. pressure, serum cholesterol or aortic atherosclerosis. ␮ By contrast, the higher dose produced a marked blocked by the addition of candesartan, 0.56 g/ml. reduction in blood pressure, that was similar to that In subsequent experiments, incubation of macro- seen with the previous study with trandolapril. This phage cultures with a logarithmic series of candesar- was associated with significant reductions in aortic tan concentrations resulted in a dose-related inhi- atherosclerosis and the cholesterol content of bition of oxidised LDL uptake (Figure 5); ␮ atherosclerotic plaques. In irbesartan-treated ani- candesartan concentrations above 0.56 g consist- mals, 24% of the aortic intimal surface was affected ently reduced uptake of oxidised LDL by 70% or by atherosclerosis, compared with 39% in control more. Such findings may have implications for clini- animals, and similar reductions were seen in the cal practice, suggesting that candesartan doses ascending, descending and abdominal aortic seg- higher than those needed to control blood pressure ments. The cholesterol content in the aorta was may offer further beneficial effects in terms of pre- decreased from 27% to 17% in irbesartan-treated vention of atherosclerosis. animals. These findings suggest that blood pressure reduction may contribute to the anti-atherogenic effects of AT1-receptor blockers. It should be noted, however, that irbesartan is not a fully insurmount- 44 able AT1-receptor antagonist, and hence it is poss- ible that the AT1-receptors were not permanently blocked in this study. As a result, some atherogenic actions of angiotensin II may still have been expressed in the presence of irbesartan. Recent studies45 have investigated the anti-athero- genic effects of candesartan, which acts as a fully 44 insurmountable AT1-receptor antagonist. In the first series of experiments, mouse macrophages from the J774A cell line were cultured and incubated for 3, 6 or 24 h with various concentrations of labelled oxidised LDL, with or without candesartan or angio- tensin II. The cells were then washed repeatedly and the remaining radioactivity counted to determine uptake of oxidised LDL. Viability studies showed that the addition of angiotensin II or candesartan had no effect on cell growth. Angiotensin II pro- Figure 5 Inhibition of uptake of oxidised LDL by murine macro- phages incubated with different concentrations of candesartan.45 duced a significant increase in the uptake of oxi- Reproduced with permission from Papademetriou V et al. Preven-

dised LDL, particularly at an oxidised LDL concen- tion of atherosclerosis by specificAT1-receptor blockade with tration of 50 ␮g/ml (Figure 4). This effect was candesartan cilexetil. JRAAS 2001; 2 (Suppl 1): S77–S80.

Journal of Human Hypertension Role of angiotensin II in atherosclerosis V Papademetriou S39 candesartan nor atenolol had any significant effect on blood pressure, compared with control animals. Candesartan treatment, however, was associated with a significant reduction in aortic atherosclerosis, compared with either atenolol-treated animals or controls (Figure 6). In the thoracic aorta the mean area covered by atherosclerotic plaques was 18% in candesartan-treated animals, compared with 49% in atenolol-treated animals and 34% in the controls. Candesartan treatment was also associated with a significant reduction in the cholesterol content of the thoracic aorta, compared with both atenolol- treated animals and controls (Figure 7). In these experiments, therefore, candesartan appeared to inhibit atherosclerosis by direct effects that were not related to changes in blood pressure.

Conclusions Figure 6 Atherosclerotic plaque formation in the aortas of Watan- abe rabbits treated for 6 months with candesartan cilexetil, Evidence from a number of sources indicates that 2 mg/kg/day, or atenolol, 10 mg/kg/day, and in control animals.45 the renin-angiotensin system contributes to the *P Ͻ 0.05 vs both; **P = 0.07 vs both. Reproduced with per- development of atherosclerosis by multiple mech- mission from Papademetriou V et al. Prevention of atheroscler- anisms. Studies in experimental animals have osis by specificAT1-receptor blockade with candesartan cilexetil. JRAAS 2001; 2 (Suppl 1): S77–S80. shown that early treatment with AT1-receptor block- ers can inhibit these mechanisms, thus preventing or reducing the development of atherosclerosis. In a second series of experiments, Watanabe rab- Moreover, studies with candesartan and losartan bits were treated for 6 months with candesartan indicate that these effects may be independent of cilexetil, 2 mg/kg/day or atenolol, 10 mg/kg/day; a changes in blood pressure. The finding that AT1- third group of animals served as controls. Blood receptor blockers may prevent the development of pressure was measured at monthly intervals. At the atherosclerosis is consistent with the findings of end of the experiment, the animals were killed with numerous large clinical outcome trials, which have pentobarbital and aortic segments removed for histo- shown that ACE inhibitors reduce cardiovascular logical examination and determination of choles- mortality and morbidity in high-risk patients. terol and atherosclerotic plaque content. Neither References 1 Forgione MA, Leopold JA, Loscalzo J. Roles of endo- thelial dysfunction in coronary artery disease. Curr Opin Cardiol 2000; 15: 409–415. 2 Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992; 326: 242–250. 3 Kannel WB. Hypertension as a risk factor for cardiac events–epidemiologic results of long-term studies. J Cardiovasc Pharmacol 1993; 21 (Suppl 2): S27–S37. 4 Neaton JD et al. Serum cholesterol level and mortality findings for men screened in the Multiple Risk Factor Intervention Trial. Multiple Risk Factor Intervention Trial Research Group. Arch Intern Med 1992; 152: 1490–1500. 5 Pyo¨ra¨la¨ K, Laakso M, Uusitupa M. Diabetes and athero- sclerosis: an epidemiologic view. Diabetes Metab Rev 1987; 3: 463–524. 6 Wilhelmsen L. Coronary heart disease: epidemiology of smoking and intervention studies of smoking. Am Heart J 1988; 115: 242–249. Figure 7 Cholesterol content in the thoracic aorta of Watanabe rabbits treated for 6 months with candesartan cilexetil, 7 Vallotton MB. The renin-angiotensin system. Trends 2 mg/kg/day, or atenolol, 10 mg/kg/day, and in control animals.45 Pharmacol Sci 1987; 8:69–74. Reproduced with permission from Papademetriou V et al. Preven- 8 Saxena PR. Interaction between the renin-angiotensin- tion of atherosclerosis by specificAT1-receptor blockade with aldosterone and sympathetic nervous systems. J candesartan cilexetil. JRAAS 2001; 2 (Suppl 1): S77–S80. Cardiovasc Pharmacol 1992; 19 (Suppl 6): S80–S88.

Journal of Human Hypertension Role of angiotensin II in atherosclerosis V Papademetriou S40 9 The MRFIT Research Group. Mortality after 10 1/2 cular disease. A unifying hypothesis. Hypertension years for hypertensive participants in the Multiple 2001; 37: 1047–1052. Risk Factor Intervention Trial. Circulation 1990; 82: 26 Keidar S, Kaplan M, Hoffman A, Aviram M. Angioten- 1616–1628. sin II stimulates macrophages-mediated oxidation of 10 Collins R et al. Blood pressure, stroke and coronary low density . Atherosclerosis 1995; 115: heart disease. Part 2, Short-term reductions in blood 201–215. pressure: overview of randomised drug trials in their 27 Keidar S, Attias J. Angiotensin II injection into mice epidemiological context. Lancet 1990; 335: 827–838. increases the uptake of oxidized LDL by their 11 Hansson L et al. Effects of intensive blood-pressure macrophages via a proteoglycan-mediated pathway. lowering and low-dose aspirin in patients with hyper- Biochem Biophys Res Comm 1997; 239:63–67. tension: principal results of the Hypertension Optimal 28 Kataoka H et al. Expression of lectinlike oxidized low- Treatment (HOT) randomised trial. Lancet 1998; 351: density lipoprotein receptor-1 in human atheroscler- 1755–1762. otic lesions. Circulation 1999; 99: 3110–3117. 12 O’Malley JP, Maslen CL, Illingworth DR. Angiotensin- 29 Mehta JL, Li D. Facilitative interaction between angio- converting enzyme and cardiovascular risk. Curr Opin tensin II and oxidised LDL in cultured human coron- Lipidol 1999; 10: 407–415. ary artery endothelial cells. JRAAS 2001; 2 (Suppl 1): 13 Akar N, Aras O, Omurlu K, Cin S. Deletion polymor- S70–S76. phism at the angiotensin-converting enzyme in Turk- 30 Funakoshi Y, Ichiki T, Ito K, Takeshita A. Induction ish patients with coronary artery disease. Scan J Clin of interleukin-6 expression by angiotensin II in rat vas- Invest 1998; 58: 491–496. cular smooth muscle cells. Hypertension 1999; 34: 14 Nakai K et al. Deletion polymorphism of the angioten- 118–125. sin I-converting enzyme gene is associated with serum 31 Schieffer B et al. Expression of angiotensin II and ACE concentration and increased risk for CAD in the interleukin 6 in human coronary atherosclerotic pla- Japanese. Circulation 1994; 90: 2199–2202. ques: potential implications for inflammation and 15 Kamitani A et al. Enhanced predictability of myocar- plaque instability. Circulation 2000; 101: 1372–1378. dial infarction in Japanese by combined genotype 32 Kranzhofer R et al. Angiotensin induces inflammatory analysis. Hypertension 1995; 25: 950–953. activation of human vascular smooth muscle cells. 16 Gardemann A et al. ACE I/D gene polymorphism: pres- Arterioscler Thromb Vasc Biol 1999; 19: 1623–1629. ence of the ACE D allele increases the risk of coronary 33 Han Y, Runge MS, Brasier AR. Angiotensin II induces artery disease in younger individuals. Atherosclerosis interleukin-6 transcription in vascular smooth muscle 1998; 139: 153–159. cells through pleiotropic activation of nuclear factor- 17 Alderman MH et al. Association of the renin-sodium kappa B transcription factors. Circ Res 1999; 84: profile with the risk of myocardial infarction in 695–703. 34 Strawn WB et al. Angiotensin II AT -receptor blockade patients with hypertension. N Engl J Med 1991; 324: 1 inhibits monocyte activation and adherence in trans- 1098–1104. genic (mRen2)27 rats. J Cardiovasc Pharmacol 1999; 18 The SOLVD Investigators. Effect of enalapril on sur- 33: 341–351. vival in patients with reduced left ventricular ejection 35 Naftilan AJ, Pratt RE, Dzau VJ. Induction of PDGF A- fractions and congestive heart failure. N Engl J Med chain and c-myc gene expression by angiotensin II in 1991; 325: 293–302. vascular smooth muscle cells. J Clin Invest 1989; 83: 19 The SOLVD Investigators. Effect of enalapril on mor- 1419–1424. tality and the development of heart failure in asympto- 36 Itoh H et al. Multiple autocrine growth factors modu- matic patients with reduced left ventricular ejection late vascular smooth muscle cell growth response to fractions. N Engl J Med 1992; 327: 685–691. angiotensin II. J Clin Invest 1993; 91: 2268–2274. 20 Pfeffer MA et al. Effect of captopril on mortality and 37 Kai M et al. The multiple actions of angiotensin II in morbidity in patients with left ventricular dysfunction atherogenesis. Regulatory Peptides 2000; 93:65–77. after myocardial infarction. Results of the survival and 38 Strawn WB et al. Inhibition of early atherogenesis by ventricular enlargement trial. The SAVE Investigators. losartan in monkeys with diet-induced hypercholes- N Engl J Med 1992; 327: 669–677. terolaemia. Circulation 2000; 101: 1586–1593. 21 Køber L et al. A clinical trial of the angiotensin-con- 39 Stary HC, Malinow MR. Ultrastructure of experimental verting-enzyme inhibitor trandolapril in patients with coronary artery atherosclerosis in cynomolgus left ventricular dysfunction after myocardial infarc- macaques. A comparison with the lesions of other pri- tion. Trandolapril Cardiac Evaluation (TRACE) Study mates. Atherosclerosis 1982; 43: 151–175. Group. N Engl J Med 1995; 333: 1670–1676. 40 Small DM et al. Physiochemical and histological 22 The Acute Infarction Ramipril Efficacy (AIRE) study changes in the arterial wall of nonhuman primates investigators. Effect of ramipril on mortality and mor- during progression and regression of atherosclerosis. J bidity of survivors of acute myocardial infarction with Clin Invest 1984; 73: 1590–1605. clinical evidence of heart failure. Lancet 1993; 342: 41 Ghosh S, Armstrong ML, Megan MB, Cheng FH. 821–828. Arterial uptake indices of low density lipoproteins 23 The Hope Study Investigators. Effects of an angioten- after fatty streak formation in Cynomolgus monkeys. sin-converting-enzyme inhibitor, ramipril, on cardio- Cardiovasc Res 1987; 21:14–20. vascular events in high-risk patients. N Engl J Med 42 Chobanian AV, Haudenschild CC, Nickerson C, Hope 2000; 342: 145–153. S. Trandolapril inhibits atherosclerosis in the Watan- 24 Fukuhara M et al. Angiotensin-converting enzyme abe heritable hyperlipidemic rabbit. Hypertension expression in human carotid artery atherosclerosis. 1992; 20: 473–477. Hypertension 2000; 35 (1 part 2): 353–359. 43 Hope S, Brecher P, Chobanian AV. Comparison of the

25 Dzau VJ. Tissue angiotensin and pathobiology of vas- effects of AT1 receptor blockade and angiotensin con-

Journal of Human Hypertension Role of angiotensin II in atherosclerosis V Papademetriou S41 verting enzyme inhibition on atherosclerosis. Am J Brunner HR (eds). Angiotensin II receptor antagonists. Hypertens 1999; 12:28–34. Hanley & Belful: Philadelphia, 2000, pp 105–118. 44 Vauquelin G, Fierens FLP, Vanderheyden PML. Dis- 45 Papademetriou V et al. Prevention of atherosclerosis

tinction between surmountable and insurmountable by specificAT1-receptor blockade with candesartan angiotensin II AT1 receptor antagonists. In: Epstein M, cilexetil. JRAAS 2001; 2 (Suppl 1): S77–S80.

Journal of Human Hypertension