pactimibe and Atherosclerosis

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.

Topics: Alkaloids; Animals; Atherosclerosis; Carbazoles; Cells, Cultured; CHO Cells; Cholesterol; Cholesterol Esters; Cricetinae; Cricetulus; Foam Cells; Humans; Hyperlipidemias; Lipoproteins, LDL; Macrophages; Mice; Mice, Inbred C57BL; Porifera; Sterol O-Acyltransferase; Sterol O-Acyltransferase 2

Topics: Atherosclerosis; Biomarkers; Clinical Trials, Phase III as Topic; Endpoint Determination; Humans; Indoleacetic Acids; Sterol O-Acyltransferase; Treatment Failure; Treatment Outcome

The objective of the present study was to determine whether a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, pactimibe sulfate (CS-505), could reduce atherosclerotic lesions beyond and independent of the reduction achieved by cholesterol lowering alone from two different types of lesions. (1) Early lesion model. Twelve-week-old apolipoprotein E (apoE)(-/-) mice were treated with 0.03 or 0.1% (w/w) CS-505, 0.1 or 0.3% avasimibe (CI-1011), or 3% cholestyramine for 12 weeks. Each treatment significantly reduced plasma cholesterol by a similar degree (43-48%). The antiatherosclerotic activity of 0.1% CS-505, however, was more efficacious than the effects of the other treatments (90% versus 40-50%). (2) Advanced lesion model. Twenty-four-week-old apoE(-/-) mice were treated with 0.03 or 0.1% CS-505 or 0.1% CI-1011 for 12 weeks. CS-505 at 0.1% revealed enhanced lesion reduction compared with 0.1% CI-1011 (77% versus 54%), whereas the plasma cholesterol-lowering effect of 0.1% CS-505 was almost the same as that of 0.1% CI-1011. Furthermore, immunohistochemical analysis demonstrated that CS-505 significantly reduced the number of macrophages and expression of matrix metalloproteinase (MMP)-2, MMP-9, and MMP-13. These data indicate that CS-505 can reduce and stabilize atherosclerotic lesions. This antiatherosclerotic activity is exerted via both cholesterol lowering and direct ACAT inhibition in plaque macrophages.

Topics: Animals; Anticholesteremic Agents; Apolipoproteins E; Atherosclerosis; Cell Line; Humans; Indoleacetic Acids; Lipids; Mice; Mice, Knockout; Monocytes; Sterol O-Acyltransferase

Novel acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitor pactimibe was administered as the sulfate salt form to 3-month-old homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits at doses of 0, 10, or 30 mg/kg for 32 weeks. Pactimibe (10 and 30 mg/kg) tended to reduce intimal thickening in thoracic aortic lesions (294+/-39 and 276+/-32 microm, respectively, versus 313+/-37 microm control), histopathological examination revealing significantly increased smooth muscle cell area (12.0+/-0.9% and 12.3+/-0.5%, P<0.05, respectively, versus 9.7+/-0.8% control), significantly increased collagen fiber area (20.5+/-1.2% and 31.0+/-1.3%, P<0.05, respectively, versus 16.2+/-1.0% control), and tended to reduce macrophage infiltration (6.0+/-1.1% and 4.6+/-1.0%, respectively, versus 7.0+/-1.3% control). Pactimibe dose-dependently reduced cholesteryl ester content in thoracic and abdominal aortic lesions, and reduced free cholesterol content in the aorta versus control. Although pactimibe did not alter serum cholesterol levels in WHHL rabbits, it stabilized vulnerable plaque characterized with reduced cholesteryl ester content, enriched collagen fibers and increased smooth muscle cells, indicating potential as a treatment strategy for coronary heart disease.

Topics: Animals; Aorta; Atherosclerosis; Cholesterol Esters; Collagen; Extracellular Matrix; Hyperlipidemias; Indoleacetic Acids; Macrophages; Muscle, Smooth, Vascular; Rabbits; Sterol O-Acyltransferase

Topics: Animals; Atherosclerosis; Coronary Thrombosis; Diabetes Mellitus, Type 2; Ethics, Clinical; Glycine; Heart Failure; Humans; Indoleacetic Acids; Myocardial Infarction; Oxazoles; Prostheses and Implants; Stroke; Treatment Failure; Ultrasonography