Acyl-CoA: Cholesterol acyltransferase inhibition reduces atherosclerosis in apolipoprotein E-deficient mice

Background-Acyl-CoA:cholesterol acyltransferase (ACAT) converts cholesterol to cholesteryl esters. The form of ACAT in macrophages, ACAT1, contributes to foam cell formation in the arterial wall and the development of atheros clerosis. Recent studies in a mouse model of atherosclerosis (the apolipopr otein E [apoE]-deficient mouse), however, have suggested that complete defi ciency of ACAT1 activity is not antiatherogenic, in part because of toxicit y resulting from adverse effects on tissue cholesterol homeostasis. We have tested whether partial inhibition of ACAT1 and ACAT2 (expressed in liver a nd intestine) activities reduces atherosclerosis development in apoE-defici ent mice and avoids toxicity. Methods and Results-ApoE-deficient mice were maintained for 17 weeks on a W estern-type diet without (control) or with the ACAT inhibitor F-1394 (effec tive against ACAT1 and ACAT2) at doses of either 300 (low) or 900 (high) mg /kg. Intimal lesion area at the aortic sinus in controls was 0.69+/-0.06 mm (2). F-1394 treatment significantly decreased lesional area by 39% (low) or 45% (high). F-1394 treatment also reduced lesional immunostaining for macr ophages by 61% (low) or 83% (high). En face analysis showed that surface li pid staining in control aortas was 20.0+/-12.8%; F-1394 treatment reduced t his by 46% (low) or 62% (high). There were no obvious signs of systemic or vessel wall toxicity associated with F-1394 treatment. Conclusions-Partial ACAT inhibition by F-1394 had antiatherogenic effects i n apoE-deficient mice that were achieved without obvious toxicity. Partial ACAT inhibition may have therapeutic potential in the clinical treatment of atherosclerosis.