Preferential pharmacological inhibition of macrophage ACAT increases plaque formation in mouse and rabbit models of atherogenesis
| Autor: | Takeo Matsukura, Jean Claude Ortuno, Shigeo Ohbayashi, Alan D Edgar, Jean Binet, Akihiro Matsuura, Thierry Laugel, Paul Padovani, Christiane Legendre, Christian Guffroy, Stéphane Perrey, Francois Bellamy, Toshiya Tanaka |
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| Rok vydání: | 2001 |
| Předmět: |
Male
Arteriosclerosis Sterol O-acyltransferase Biology Pharmacology Monocytes Mice chemistry.chemical_compound Apolipoproteins E Piperidines Microsomes Tumor Cells Cultured medicine Animals Macrophage Anilides Enzyme Inhibitors Receptor Aorta Foam cell Mice Knockout Monocyte Animal Feed Dietary Fats Mice Inbred C57BL medicine.anatomical_structure Receptors LDL chemistry Biochemistry Macrophages Peritoneal Microsomes Liver Cholesteryl ester Diet Atherogenic Female lipids (amino acids peptides and proteins) Cholesterol Esters Rabbits Cardiology and Cardiovascular Medicine Ex vivo Intracellular Foam Cells Sterol O-Acyltransferase |
| Zdroj: | Atherosclerosis. 155:359-370 |
| ISSN: | 0021-9150 |
| DOI: | 10.1016/s0021-9150(00)00599-2 |
| Popis: | The cholesteryl ester, foam cell-enriched vulnerable plaque is a principle pharmacological target for reducing athero-thrombosis. Acyl CoA:cholesterol Acyl Transferase (ACAT) catalyzes the esterification of free cholesterol in intestine, liver, adrenal and macrophages, leading in the latter cells to intracellular cholesteryl ester accumulation and foam cell formation in the arterial intima. Previous studies suggested the existence of several isoforms of ACAT with different tissue distribution and this has largely been confirmed by molecular cloning of ACAT-1 and ACAT-2. We developed a series of ACAT inhibitors that preferentially inhibited macrophage ACAT relative to hepatic or intestinal ACAT based on in vitro assays and ex vivo bioavailability studies. Four of these compounds were tested in three models of atherosclerosis at oral doses shown to give sufficient bioavailable monocyte/macrophage ACAT inhibitory activity. In fat-fed C57BL/6 mice, chow fed apo E-/- mice and KHC rabbits, the various ACAT inhibitors had either no effect or increased indices of atherosclerotic foam cell formation. Direct and indirect measurements suggest that the increase in plaque formation may have been related to inhibition of macrophage ACAT possibly leading to cytotoxic effects due to augmented free cholesterol. These results suggest that pharmacological inhibition of macrophage ACAT may not reduce, but actually aggravate, foam cell formation and progression. |
| Databáze: | OpenAIRE |
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