Effect of probucol on serum lipids, atherosclerosis and toxicology in fat-fed LDL receptor deficient mice

Although numerous transgenic mouse models for atherosclerosis have been dev eloped recently, little is known about their response to hypolipidaemic or anti-atherosclerotic agents. We investigated the effect of the known hypoch olesterolaemic and anti-atherosclerotic drug probucol on serum lipids, lipo proteins and atherosclerosis in fat-fed low density lipoprotein (LDL) recep tor deficient mice. Probucol at doses of 0.2 and 1% in the diet which are s imilar to those used in the mouse by other investigators reduced serum chol esterol by 26 and 37%, respectively. Probucol also reduced serum triglyceri de levels by 33 and 47% at doses of 0.2 and 1%, respectively. The decrease in serum cholesterol and triglycerides was mainly due to a decrease of thes e lipids in VLDL and or chylomicrons. Despite these potentially beneficial changes in serum lipids atherosclerotic lesion areas in the aortic root wer e unchanged in the probucol treated mice. After 12 weeks treatment most of the mice receiving probucol had swollen feet and tails due to oedema. Histo logical examination of the base of the hearts from the probucol treated mic e revealed lipid droplets within the reticuloendothelial and other intersti tial cells. There was also an interstitial subacute inflammatory cell infil tration associated with the lipid deposition. The oedema induced by probuco l could be the result of cardiac insufficiency due to interstitial lipidosi s and inflammation in the base of the heart together with the extensive ath erosclerotic lesions in the aortic sinus. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.