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Olmesartan and pravastatin additively reduce development of atherosclerosis in APOE*3Leiden transgenic mice

Author: Hoorn, J.W.A. van der · Kleemann, R. · Havekes, L.M. · Kooistra, T. · Princen, H.M.G. · Jukema, J.W.
Type:article
Date:2007
Institution: TNO Kwaliteit van Leven
Source:Journal of Hypertension, 12, 25, 2454-2462
Identifier: 240502
doi: doi:10.1097/HJH.0b013e3282ef79f7
Keywords: Biology · Biomedical Research · APOE*3Leiden mice · Atherosclerosis · Combination therapy · Olmesartan · Pravastatin · T lymphocyte · transgenic mouse · Angiotensin II Type 1 Receptor Blockers · Animals · Apolipoprotein E3 · Atherosclerosis · Blood Pressure · Collagen · Diet, Atherogenic · Drug Synergism · Female · Humans · Hydroxymethylglutaryl-CoA Reductase Inhibitors · Imidazoles · Inflammation · Lipids · Macrophages · Mice · Mice, Transgenic · Monocytes · Muscle, Smooth, Vascular · Pravastatin · Recombinant Proteins · Serum Amyloid A Protein · T-Lymphocytes · Tetrazoles

Abstract

AIM: This study was designed to investigate the effect of the angiotensin II receptor blocker olmesartan alone, or in combination with standard treatment with a statin, pravastatin, on atherosclerosis development in APOE*3Leiden transgenic mice. METHODS AND RESULTS: Four groups of 15 mice received an atherogenic diet alone (plasma cholesterol 17.4 ± 2.7 mmol/l) or supplemented with either 0.008% (w/w) olmesartan (9.3 mg/kg per day) (plasma cholesterol 16.4 ± 3.9 mmol/l), 0.03% (w/w) pravastatin (35 mg/kg per day) (plasma cholesterol 14.6 ± 2.6 mmol/l), or the combination of both (plasma cholesterol 14.5 ± 2.9 mmol/l) for 6 months. Treatment with olmesartan or pravastatin reduced the development of atherosclerosis as compared to the control group (-46 and -39%, respectively). Pravastatin also reduced the severity of the lesions. As compared to control the combination of both treatments almost fully prevented atherosclerosis (-91%, P < 0.001) and strongly reduced lesion number (-69%), lesion severity (-79%), number of macrophages (-89%) and T lymphocytes (-86%) per cross-section. Treatment with olmesartan alone and in combination with pravastatin inhibited the adhesion of monocytes to the vessel wall (-22%; P < 0.05 and -25%; P < 0.01, respectively), and reduced the relative quantity of macrophages in the lesions (-38%; P < 0.05 and -26%; NS, respectively) as compared to control. CONCLUSION: Olmesartan reduced atherosclerosis development mainly by decreasing monocyte adhesion and the relative amount of macrophages, whereas pravastatin inhibited the progression of atherosclerosis to more advanced lesions, reflecting different anti-atherosclerotic modes of action of the two drugs. Combination therapy with olmesartan and pravastatin additively reduced atherosclerosis development, resulting in less and less severe lesions. © 2007 Lippincott Williams & Wilkins, Inc.