Manzamine A, a marine-derived alkaloid, inhibits accumulation of cholesterol ester in macrophages and suppresses hyperlipidemia and atherosclerosis in vivo

The formation of foam cells in macrophages plays an essential role in the progression of early atherosclerotic lesions and therefore its prevention is considered to be a promising target for the treatment of atherosclerosis. We found that an extract of the marine sponge Acanthostrongylophora ingens inhibited the foam cell formation induced by acetylated low-density lipoprotein (AcLDL) in human monocyte-derived macrophages, as measured based on the accumulation of cholesterol ester (CE). Bioassay-guided purification of inhibitors from the extract afforded manzamines. Manzamine A was the most potent inhibitor of foam cell formation, and also suppressed CE formation in Chinese hamster ovary cells overexpressing acyl-CoA:cholesterol acyl-transferase (ACAT)-1 or ACAT-2. In addition, manzamine A inhibited ACAT activity. Next, we orally administered manzamine A to apolipoprotein E (apoE)-deficient mice for 80 days, and found that total cholesterol, free cholesterol, LDL-cholesterol, and triglyceride levels in serum were significantly reduced and the area of atherosclerotic lesions in the aortic sinus was also substantially diminished. These findings clearly suggest that manzamine A suppresses hyperlipidemia and atherosclerosis in apoE-deficient mice by inhibiting ACAT and is therefore a promising lead compound in the prevention or treatment of atherosclerosis. Although manzamine A has been reported to show several biological activities, this is the first report of a suppressive effect of manzamine A on atherosclerosis in vivo.