Background-In clinical studies, sphingomyelin (SM) plasma levels correlated with the occurrence of coronary heart disease independently of plasma cholesterol levels. We hypothesized that inhibition of SM synthesis would have antiatherogenic effects. To test this hypothesis, apolipoprotein E (apoE)-knockout (KO) mice were treated with myriocin, a potent inhibitor of serine palmitoyltransferase, the rate-limiting enzyme in SM biosynthesis. Methods and Results-Diet-admix treatment of apoE-KO mice with myriocin in Western diet for 12 weeks lowered SM and sphinganine plasma levels. Decreases in sphinganine and SM concentrations were also observed in the liver and aorta of myriocin-treated animals compared with controls. Inhibition of de novo sphingolipid biosynthesis reduced total cholesterol and triglyceride plasma levels. Cholesterol distribution in lipoproteins demonstrated a decrease in ␤-VLDL and LDL cholesterol and an increase in HDL cholesterol. Oil red O staining of total aortas demonstrated reduction of atherosclerotic lesion coverage in the myriocin-treated group. Atherosclerotic plaque area was also reduced in the aortic root and brachiocephalic artery. Conclusions-Inhibition of de novo SM biosynthesis in apoE-KO mice lowers plasma cholesterol and triglyceride levels, raises HDL cholesterol, and prevents development of atherosclerotic lesions.

Due to the potential importance of acyl-coenzyme A:cholesterol 0-acyltransferase (ACAT) in the generation of lipid-filled monocytes-macrophages, the ACAT inhibitor CI-976 (2,2-dimethyl-AT-(2,4,6-trimethoxyphenyl)dodecanamide) was evaluated relative to selected lipidlowering agents for their effect on atherosclerotic lesion regression and progression. Atherosclerotic lesions comparable in composition to human fatty streaks were induced by chronic endothelial denudation in the iliac-femoral artery of hypercholesterolemic New Zealand White rabbits before intervention, while naturally occurring fatty streaks developed in the thoracic aorta. CI-976 administered in a hypercholesterolemic diet at a dose that did not lower plasma cholesterol prevented the accumulation of monocytes-macrophages within the preestablished iliac-femoral lesion and reduced the foam cell area by 27-29% relative to the initiation of intervention. CI-976 also blunted the development of thoracic aortic fatty streak-like lesions and decreased the cholesteryl ester enrichment by 46%. CI-976 had no effect on plasma triglycerides and, more importantly, had no effect or decreased liver, iliac-femoral, and thoracic aortic free cholesterol content Dietary intervention alone increased monocytemacrophage involvement in the iliac-femoral lesion despite reductions in plasma, liver, and thoracic aortic cholesterol content Conventional lipid-lowering therapy such as cholestyramine or cholestyramine/niacin required substantial decreases in plasma cholesterol levels to achieve comparable vascular changes. We conclude that inhibition of ACAT within the arterial wall by the potent and specific ACAT inhibitor CI-976, even in the absence of plasma cholesterol lowering, can result in the inhibition of atherosclerotic lesion progression and can enhance regression. (Arteriosclerosis and Thrombosis 1991;ll:1830-1843) A cyl-coenzyme A: cholesterol O-acyltransferase / \ (EC 2.3.1.26; ACAT), the primary enzyme JL \~ responsible for the esterification of cholesterol in all mammalian cells, has been implicated as a key enzyme involved in cholesterol absorption, very low density lipoprotein secretion, and the formation of lipid-filled macTophages and smooth muscle cells (SMCs).1 In addition, monocyte-macrophage foam cells have been shown to be integral components of human and animal atherosclerosis. In humans, both Received March 19, 1991; revision accepted August 19, 1991. fatty streaks and fibrous plaques are characterized by the presence of lipid-filled macrophages; however, in fibrous plaques the appearance of abundant extracellular lipid and lipid-filled SMCs is also noted. 2 Several investigators, using monoclonal antibodies to monocytes-macrophages, have shown that monocytes-macrophages in animals are involved in the initiation and development of the fatty streak and the conversion to the fibrous plaque. "10 Since ACAT is responsible for the esterification and storage of cholesterol in the macrophage, one might hypothesize that inhibition of arterial wall ACAT may ...

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