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Effect of low dose atorvastatin versus diet-induced cholesterol lowering on atherosclerotic lesion progression and inflammation in apolipoprotein E*3-Leiden transgenic mice

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Author: Verschuren, L. · Kleemann, R. · Offerman, E.H. · Szalai, A.J. · Emeis, S.J. · Princen, H.M.G. · Kooistra, T.
Type:article
Date:2005
Institution: TNO Kwaliteit van Leven
Source:Arteriosclerosis, Thrombosis, and Vascular Biology, 1, 25, 161-167
Identifier: 238267
doi: doi:10.1161/01.ATV.0000148866.29829.19
Keywords: Biology · Biomedical Research · Growth factors · Lipids · Lipoprotein metabolism · Pathophysiology · C reactive protein · Cholesterol · Gelatinase B · Macrophage migration inhibition factor · Plasminogen activator inhibitor 1 · Vascular cell adhesion molecule 1 · Animal cell · Animal experiment · animal model · Antiinflammatory activity · Aorta arch · Cholesterol blood level · Cholesterol diet · Controlled study · Dietary intake · Disease activity · Disease course · Disease severity · Inflammation · Lipoprotein metabolism · Low drug dose · Macrophage · Monocyte · Mouse · Nonhuman · Pathophysiology · Protein expression · Smooth muscle fiber · Transgenic mouse · Treatment outcome · Amyloid A protein · Apolipoprotein E3 · Atorvastatin · Animals · Anticholesteremic Agents · Aorta · Apolipoprotein E3 · Apolipoproteins E · Arteriosclerosis · Biological Markers · C-Reactive Protein · Cholesterol · Diet · Diet, Atherogenic · Drug Administration Schedule · Female · Heptanoic Acids · Inflammation · Male · Mice · Mice, Transgenic · Pyrroles · Serum Amyloid A Protein

Abstract

Objective - To evaluate whether low-dose atorvastatin suppresses atherosclerotic lesion progression and inflammation in apolipoprotein E*3 (apoE*3)-Leiden mice beyond its cholesterol-lowering effect. Methods and Results - ApoE*3-Leiden mice were fed a high-cholesterol (HC) diet until mild atherosclerotic lesions had formed. Subsequently, HC diet feeding was continued or mice received HC supplemented with 0.002% (w/w) atorvastatin (HC+A), resulting in 19% plasma cholesterol lowering, or mice received a low-cholesterol (LC) diet to establish a plasma cholesterol level similar to that achieved in the HC+A group. HC+A and LC diet reduced, significantly and to the same extent, lesion progression and complication in the aortic root, as assessed by measuring total atherosclerotic lesion area, lesion severity, and macrophage and smooth muscle cell area. In the aortic arch, HC+A but not LC blocked lesion progression. HC+A and LC reduced vascular inflammation (ie, expression of macrophage migration inhibitory factor, plasminogen activator inhibitor-1, matrix metalloproteinase-9), but HC+A additionally suppressed vascular cell adhesion molecule-1 expression and, in parallel, monocyte adhesion. In contrast, low-dose atorvastatin showed no antiinflammatory action toward hepatic inflammation markers (serum amyloid A, C-reactive protein [CRP]) in apoE*3-Leiden mice and human CRP transgenic mice. Conclusion - Low-dose atorvastatin cholesterol-dependently reduces lesion progression in the aortic root but shows antiinflammatory vascular activity and tends to retard atherogenesis in the aortic arch beyond its cholesterol-lowering effect. Chemicals / CAS: amyloid A protein, 59165-71-8; atorvastatin, 134523-00-5, 134523-03-8; C reactive protein, 9007-41-4; cholesterol, 57-88-5; gelatinase B, 146480-36-6; plasminogen activator inhibitor 1, 140208-23-7; Anticholesteremic Agents; apolipoprotein E3 (Leidein); Apolipoprotein E3; Apolipoproteins E; atorvastatin, 110862-48-1; Biological Markers; C-Reactive Protein, 9007-41-4; Cholesterol, 57-88-5; Heptanoic Acids; Pyrroles; Serum Amyloid A Protein