Preferential pharmacological inhibition of macrophage ACAT increases plaque formation in mouse and rabbit models of atherogenesis

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 i n intestine, liver, adrenal and macrophages, leading in the latter cells to intracellular cholesteryl ester accumulation and foam cell formation in th e: arterial intima. Previous studies suggested the existence of several iso forms of ACAT with different tissue distribution and this has largely been confirmed by molecular cloning of ACAT-I and ACAT-2. We developed a series of ACAT inhibitors that preferentially inhibited macrophage ACAT relative t o hepatic or intestinal ACAT based on in vitro assays and ex vivo bioavaila bility studies. Four of these compounds were tested in three models of athe rosclerosis at oral doses shown to give sufficient bioavailable monocyte/ma crophage 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 o r increased indicts of atherosclerotic foam cell formation. Direct and indi rect measurements suggest that the increase in plaque formation may have be en related to inhibition of macrophage ACAT possibly leading to cytotoxic e ffects due to augmented free cholesterol. These results suggest that pharma cological inhibition of macrophage ACAT may nut reduce, but actually aggrav ate, foam cell formation and progression. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.