The Angiotensin-II Receptor Antagonist, Losartan, Inhibits LDL Lipid Peroxidation and Atherosclerosis in Apolipoprotein E-Deficient Mice

Keidar, Shlomo; Attias, Judith; Smith, Jonathan; Breslow, Jan L.; Hayek, Tony

doi:10.1006/bbrc.1997.6844

Cited by 129 publications

(84 citation statements)

References 30 publications

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“…35 In contrast, administration of ACE inhibitors abolished macrophage recruitment in this experimental model, 36,37 and blockade of the AT 1 receptor by losartan was shown to prevent the accumulation of oxidative reactants, which abolished lipid peroxidation and the progression of atherosclerosis in an apolipoprotein E-deficient animal model. 38,39 The present study may have potential clinical implications by pointing to mechanisms by which ACE inhibitors reduce the incidence of reinfarctions, that is, the attenuation of proinflammatory processes in atherosclerotic plaques. If so, ACE inhibition should reduce serum markers of inflammation in patients treated with ACE inhibitors.…”

Section: Discussionmentioning

confidence: 86%

Expression of Angiotensin II and Interleukin 6 in Human Coronary Atherosclerotic Plaques

et al. 2000

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Background-Patients with an activated renin-angiotensin system (RAS) or genetic alterations of the RAS are at increased risk of myocardial infarction (MI). Administration of ACE inhibitors reduces the risk of MI, and acute coronary syndromes are associated with increased interleukin 6 (IL-6) serum levels. Accordingly, the present study evaluated the expression of angiotensin II (Ang II) in human coronary atherosclerotic plaques and its influence on IL-6 expression in patients with coronary artery disease. Methods and Results-Immunohistochemical colocalization of Ang II, ACE, Ang II type 1 (AT 1 ) receptor, and IL-6 was examined in coronary arteries from patients with ischemic or dilated cardiomyopathy undergoing heart transplantation (nϭ12), in atherectomy samples from patients with unstable angina (culprit lesion; nϭ8), and in ruptured coronary arteries from patients who died of MI (nϭ13). Synthesis and release of IL-6 was investigated in smooth muscle cells and macrophages after Ang II stimulation. Colocalization of ACE, Ang II, AT 1 receptor, and IL-6 with CD68-positive macrophages was observed at the shoulder region of coronary atherosclerotic plaques and in atherectomy tissue of patients with unstable angina. Ang II was identified in close proximity to the presumed rupture site of human coronary arteries in acute MI. Ang II induced synthesis and release of IL-6 shortly after stimulation in vitro in macrophages and rat smooth muscle cells. Conclusions-Ang II, AT 1 receptor, and ACE are expressed at strategic sites of human atherosclerotic coronary arteries, suggesting that Ang II is produced primarily by ACE within coronary plaques. The observation that Ang II induces IL-6 and their colocalization with the AT 1 receptor and ACE is consistent with the notion that the RAS may contribute to inflammatory processes within the vascular wall and to the development of acute coronary syndromes. (Circulation. 2000;101:1372-1378.)Key Words: interleukins Ⅲ angiotensin Ⅲ angina Ⅲ myocardial infarction Ⅲ arteries Ⅲ receptors R upture of atherosclerotic plaques occurs predominantly at the edges of the plaque's fibrous cap, the shoulder region, that is, areas of accumulated inflammatory cells, for example, macrophages, T-lymphocytes, and mast cells in close proximity to vascular smooth muscle cells (SMC). [1][2][3][4][5][6] The activated inflammatory cells stimulate their neighboring cells to erode the extracellular matrix through the release of inflammatory cytokines. The decay of the framework that forms the plaque cap leads to plaque rupture 1,7,8 and resembles the morphological correlate of an acute coronary syndrome. Serum levels of interleukin 6 (IL-6) are increased in patients with unstable angina 9 and may trigger the onset of an acute coronary syndrome. 10 IL-6 is known to be involved in the stimulation of matrix-degrading enzymes, for example, metalloproteinases. 11In parallel, the renin-angiotensin system (RAS) has been suggested to be involved in the development of acute coronary syndromes, based on the observat...

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Section: Discussionmentioning

confidence: 86%

Expression of Angiotensin II and Interleukin 6 in Human Coronary Atherosclerotic Plaques

et al. 2000

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“…The AT 1 blocker losartan was initially shown to reduce lesion size in the cholesterol-fed cynomolgus monkey. 17 More recent studies with either high-dose losartan (25 mg/kg per day) 9 or irbesartan (50 mg/kg per day) 8 were reported to attenuate atherosclerosis in nondia- betic apoE-null mice. However, another experiment in which losartan was used had findings similar to those seen in the present study, with no effect of the AT 1 antagonist on atherosclerosis in nondiabetic apoE-null mice.…”

Section: Discussionmentioning

confidence: 99%

Irbesartan but Not Amlodipine Suppresses Diabetes-Associated Atherosclerosis

Candido¹,

Allen²,

Lassila³

et al. 2004

Circulation

192

165

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Background-It remains controversial whether specific blockade of the renin-angiotensin system confers superior antiatherosclerotic effects over other antihypertensive agents in diabetes. Therefore, the aim of this study was to compare equihypotensive doses of the angiotensin II subtype 1 (AT 1 ) receptor blocker irbesartan with the calcium antagonist amlodipine on diabetes-induced plaque formation in the apolipoprotein E (apoE)-null mouse and to explore molecular and cellular mechanisms linked to vascular protection. Methods and Results-Diabetes was induced by injection of streptozotocin in 6-week-old apoE-null mice. Diabetic animals were randomized to no treatment, irbesartan, or amlodipine for 20 weeks. Diabetes was associated with an increase in plaque area and complexity in the aorta in association with a significant increase in aortic AT 1 receptor expression, cellular proliferation, collagen content, macrophage-and ␣-smooth muscle actin-positive cell infiltration, as well as an increased expression of platelet-derived growth factor-B (PDGF-B), monocyte chemoattractant protein-1 (MCP-1), and vascular cell adhesion molecule-1 (VCAM-1). Irbesartan but not amlodipine treatment attenuated the development of atherosclerosis, collagen content, cellular proliferation, and macrophage infiltration as well as diabetes-induced AT 1 receptor, PDGF-B, MCP-1, and VCAM-1 overexpression in the aorta despite similar blood pressure reductions by both treatments. Conclusions-Diabetes-associated atherosclerosis is ameliorated by AT 1 receptor blockade but not by calcium channel antagonism, providing further evidence for the vascular renin-angiotensin system playing a pivotal role in the development and acceleration of atherosclerosis in diabetes.

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“…The use of these well-defined transgenic models permits a systematic evaluation of the changes at the cellular and molecular level that occur within the lesion, and offers a small animal model in which pharmacologic interventions can be evaluated during the preclinical assessment of compounds that proceed to clinical trials. Using this approach, for example, the effects of estrogen, probucol and the angiotensin II receptor antagonist Losartan 12,32,36 have been evaluated in the apoE knockout, and with probucol, in the LDL receptor knockout. 32 Whereas both Losartan and pharmacologic doses of 17␤-estradiol reduced lesion size in the apoE knockout, probucol actually increased lesion size in both of these models.…”

Section: Discussionmentioning

confidence: 99%

“…32 Whereas both Losartan and pharmacologic doses of 17␤-estradiol reduced lesion size in the apoE knockout, probucol actually increased lesion size in both of these models. 12,32,36,37 Clearly, the mechanisms involved in the atheroprotective effects of these agents, including effects on vascular function as well as on lipoprotein oxidation and catabolism, remain to be defined. Estrogen, for example, was reported to decrease total serum cholesterol in both the apoE knockout 12,19 and in nontransgenic mouse strains, yet in contrast to the rat did not result in an upregulation of hepatic LDL receptors.…”

Section: Discussionmentioning

confidence: 99%

Estrogen-Mediated Increases in LDL Cholesterol and Foam Cell–Containing Lesions in Human ApoB100×CETP Transgenic Mice

Zuckerman

Evans

Schelm

et al. 1999

ATVB

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Abstract-The murine double transgenic mouse expressing both human apoB100 and cholesteryl ester transfer protein (CETP), has been used as a model to understand the effects mediated by various therapeutic modalities on serum lipoproteins and on atherosclerotic lesion progression. In the present study the effects of estrogen therapy on serum lipoproteins were investigated after mice were placed on an atherosclerotic diet. The daily oral administration of 20 or 100 g/kg of 17 ␣-ethinyl estradiol resulted in a significant, dose-dependent increase in LDL cholesterol over a 20-week regimen. These differences were apparent by 6 weeks and further increases were observed through the 20-week period. Although CETP did result in a reduction in total HDL, estrogen did not have any impact on the amount of CETP activity associated with the HDL particles. The significant increase in LDL cholesterol was associated with increases in the amount of apoB100 and B48 and apoE-containing particles. Hepatic apoB message levels, however, were not different between the experimental groups. Although the extent of atherosclerotic lesions was modest, Ͻ0.5% of the aortic surface area in the vehicle group, the high-dose estrogen group, showed an increase in lesion area consistent with the elevation in LDL cholesterol. These lesions, primarily restricted to the aortic root and aortic semilunar valves, were more intensely stained with Oil Red O in the high-dose estrogen group when compared with the vehicle controls. (Arterioscler Thromb

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The Angiotensin-II Receptor Antagonist, Losartan, Inhibits LDL Lipid Peroxidation and Atherosclerosis in Apolipoprotein E-Deficient Mice

Cited by 129 publications

References 30 publications

Expression of Angiotensin II and Interleukin 6 in Human Coronary Atherosclerotic Plaques

Expression of Angiotensin II and Interleukin 6 in Human Coronary Atherosclerotic Plaques

Irbesartan but Not Amlodipine Suppresses Diabetes-Associated Atherosclerosis

Estrogen-Mediated Increases in LDL Cholesterol and Foam Cell–Containing Lesions in Human ApoB100×CETP Transgenic Mice

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