The hyperlipemic hamster ‐ a model for testing the anti‐atherogenic effect of amlodipine

Sima, Anca V.; Stancu, Camelia S.; Constantinescu, E; Ologeanu, Laura; Simionescu, Maya

doi:10.1111/j.1582-4934.2001.tb00148.x

Cited by 23 publications

(20 citation statements)

References 20 publications

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“…10 In the hyperlipidemic nondiabetic hamster, amlodipine limited the size and extent of atherosclerotic plaque. 23 However, although irbesartan and another calcium channel blocker, lacidipine, have been shown to reduce plaque size in the nondiabetic apoE-null mouse, 8,10 amlodipine failed to reduce plaque area in the diabetic context. Diabetes-induced accelerated plaque formation in the aorta of the diabetic apoE-null mice was associated with a significant increase in collagen content, infiltration of vascular smooth muscle cells and macrophages, and cellular proliferation.…”

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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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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“…In this study, we have examined the role of monocytes/ macrophages in the early inflammatory stage associated with atherosclerosis of the aortic valves by employing a well-characterised experimental model: the hyperlipemic hamster Sima et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Effect of depletion of monocytes/macrophages on early aortic valve lesion in experimental hyperlipidemia

Calin¹,

Manduteanu

Dragomir

et al. 2009

Cell Tissue Res

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Monocytes/macrophages are key players throughout atheroma development. The aim of this study was to determine the role of macrophages in lesion formation in heart valves in hyperlipidemia. We examined whether systemic depletion of monocytes/macrophages had a beneficial or adverse effect on the development of lesions in hyperlipemic hamsters injected twice weekly (for 2 months) with clodronate-encapsulated liposomes (H+Lclod), a treatment that selectively induces significant monocyte apoptosis. Hyperlipemic hamsters were employed as controls, as were hyperlipemic hamsters treated with plain liposomes. We assayed serum cholesterol (CH) and triglycerides (TG), the lipid and collagen contents and the size of the valve lesions, the matrix metalloproteinases (MMPs) in the serum and vessel wall, apolipoprotein E (ApoE), interleukin-1beta (IL-1beta), and superoxide anion production. In comparison with controls, H+Lclod hamsters exhibited: (1) increased lipid and collagen accumulation within the lesions, (2) decreased activity of MMP-9 and MMP-2 in sera and aortic homogenates, (3) decreased serum CH and TG and decreased expression of ApoE in sera and liver, (4) reduced expression of IL-1beta in aorta and liver homogenates, and (5) no change in the level of superoxide anion in the aorta. Thus, initially, the presence of the macrophages is beneficial in valvular lesion formation. Depletion of monocytes/macrophages is a two-edged sword having a beneficial effect by decreasing the expression of IL-1beta and MMP activities but an adverse effect by inducing a significant increase in the lipid and collagen content and expansion of valvular lesions.

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“…In one of those studies, amlodipine caused a significant and dose-dependent reduction in lesion formation in the thoracic aorta, 1 whereas in another, it exhibited an atheroprotective effect by acting as an antioxidant and reducing LDL uptake by the vessel wall, which consequently limited the size and extent of lesional areas. 3 These two findings have been proposed to show potential mechanisms for the antiatherosclerotic effect of amlodipine. In addition to those findings, the results of several in vitro studies also indicate that treatment with amlodipine enhances nitric oxide production in endothelial cells, 4 suggesting an anti-inflammatory role for the compound.…”

mentioning

confidence: 99%

Amlodipine Modulates THP-1 Cell Adhesion to Vascular Endothelium via Inhibition of Protein Kinase C Signal Transduction

Morita

Shimokado

et al. 2003

Hypertension

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Abstract-Inflammatory responses play an important role in atherosclerosis. To critically assess the effect of dihydropyridines in inflammatory reactions, we conducted a monocyte-endothelial adhesion assay with monocytic THP-1 cells treated with amlodipine under flow conditions in vitro. THP-1 cells were incubated in the presence of amlodipine (10 mol/L) for 48 hours and then perfused over activated (interleukin-1␤, 10 U/mL, 4 hours) human umbilical vein endothelial cells. The adhesion of THP-1 cells was significantly reduced after amlodipine treatment (PϽ0.001); however, flow cytometric analysis reveled that the expression levels of integrins in THP-1 cells were not significantly altered. Furthermore, Western blotting analysis of THP-1 cell lysates revealed that translocation of RhoA from the cytosol to the membrane was significantly diminished after amlodipine treatment. In addition, activation of protein kinase C-␣ and -␤, as well as intracellular calcium influx, induced by phorbol 12-myristate 13-acetate, was diminished after amlodipine treatment. Pretreatment of THP-1 cells with calphostin C, a potent inhibitor of protein kinase C, significantly reduced THP-1 adhesion to vascular endothelium, whereas activation of ␤ 1 -integrin was reduced after amlodipine treatment in THP-1 cells, based on the immunoreactivity of an activation-specific antibody for ␤ 1 -integrin. Similar inhibitory effects were observed when we used freshly isolated peripheral blood mononuclear cells. These findings suggest a potential role for amlodipine in monocyte-endothelial interactions by modulation of protein kinase C-and RhoA-dependent mechanisms, which might account for its vascular protective effects. Key Words: calcium channel blockers Ⅲ cell adhesion molecules Ⅲ monocytes Ⅲ protein kinases Ⅲ signal transduction L -type calcium channel antagonists are widely used in the management of hypertension as well as coronary heart diseases, and an increasing number of reports support the therapeutic benefits of these compounds for patients with cardiovascular diseases. Recently, amlodipine, a Ca 2ϩ channel blocker, was shown to reduce the progression of atherosclerotic plaque formation in rabbit models, 1,2 suggesting its role in atherosclerosis. In one of those studies, amlodipine caused a significant and dose-dependent reduction in lesion formation in the thoracic aorta, 1 whereas in another, it exhibited an atheroprotective effect by acting as an antioxidant and reducing LDL uptake by the vessel wall, which consequently limited the size and extent of lesional areas. 3 These two findings have been proposed to show potential mechanisms for the antiatherosclerotic effect of amlodipine. In addition to those findings, the results of several in vitro studies also indicate that treatment with amlodipine enhances nitric oxide production in endothelial cells, 4 suggesting an anti-inflammatory role for the compound. In the present study, we attempted to elucidate the molecular mechanism responsible for the anti-inflammatory role of amlodipine by...

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The hyperlipemic hamster ‐ a model for testing the anti‐atherogenic effect of amlodipine

Cited by 23 publications

References 20 publications

Irbesartan but Not Amlodipine Suppresses Diabetes-Associated Atherosclerosis

Irbesartan but Not Amlodipine Suppresses Diabetes-Associated Atherosclerosis

Effect of depletion of monocytes/macrophages on early aortic valve lesion in experimental hyperlipidemia

Amlodipine Modulates THP-1 Cell Adhesion to Vascular Endothelium via Inhibition of Protein Kinase C Signal Transduction

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