Bocan T M, Krause B R, Rosebury W S, Mueller S B, Lu X, Dagle C, Major T, Lathia C, Lee H
Departments of Cardiovascular Therapeutics , Parke-Davis Pharmaceutical Research, Division of Warner-Lambert, 2800 Plymouth Rd, Ann Arbor, MI 48105, USA.
Arterioscler Thromb Vasc Biol. 2000 Jan;20(1):70-9. doi: 10.1161/01.atv.20.1.70.
Given the significance of cholesteryl ester (CE) accumulation in macrophage foam cell formation, we hypothesized that inhibitors of acyl-CoA:cholesterol O-acyltransferase (ACAT) would produce a histologically stable lesion by limiting macrophage enrichment and thereby a source of matrix metalloproteinases (MMPs). Male New Zealand White rabbits were sequentially fed a cholesterol/fat diet for 9 weeks, a fat-only diet for 6 weeks, and 25 mg/kg avasimibe for 7 to 8 weeks. Avasimibe had no effect on plasma total cholesterol exposure. Plasma avasimibe maximal concentration and 24-hour area-under-the-curve levels were 178 ng/mL and 2525 ng. h/mL, respectively, after 7 weeks of treatment with 25 mg/kg avasimibe. The median inhibitory concentration against human monocyte-macrophage ACAT was 12 ng/mL when determined in the absence of albumin, and aortic arch avasimibe levels were 25 ng/g of tissue wet weight. Avasimibe reduced thoracic aortic and iliac-femoral CE content by 39%, the extent of thoracic aortic lesions by 41%, aortic arch cross-sectional lesions area by 35%, and monocyte-macrophage area by 27%. The reduction in monocyte-macrophage area reflected a change in cell number and not cell size. In the iliac-femoral artery, avasimibe decreased monocyte-macrophage content by 77% and reduced the macrophage-to-lesion ratio from 0.16 to 0.05. Within the aortic arch, the catalytic activity of latent and active MMP-9 was reduced by 65% and 33%, respectively; latent and active MMP-1 and MMP-3 activity measured collectively was decreased by 52% and 60%, respectively, and MMP-2 was unchanged. Aortic arch MMP-9, tissue inhibitor of matrix metalloproteinase (TIMP)-1, and TIMP-2 mRNA levels were reduced 29% to 39%, and MMP-2 mRNA levels increased. We conclude that the bioavailable ACAT inhibitor avasimibe can directly limit macrophage accumulation, resulting in the histological appearance of mainly fibromuscular lesions, and can potentially stabilize preestablished atherosclerotic lesions by reducing MMP expression within the lesion.
鉴于胆固醇酯（CE）积累在巨噬细胞泡沫细胞形成中的重要性，我们推测酰基辅酶A：胆固醇O-酰基转移酶（ACAT）抑制剂会通过限制巨噬细胞富集，从而限制基质金属蛋白酶（MMP）的来源，产生组织学上稳定的病变。雄性新西兰白兔先后接受9周的胆固醇/脂肪饮食、6周的纯脂肪饮食，以及7至8周的25 mg/kg阿伐他汀治疗。阿伐他汀对血浆总胆固醇暴露无影响。用25 mg/kg阿伐他汀治疗7周后，血浆阿伐他汀的最大浓度和24小时曲线下面积水平分别为178 ng/mL和2525 ng·h/mL。在无白蛋白存在的情况下测定时，对人单核细胞-巨噬细胞ACAT的半数抑制浓度为12 ng/mL，主动脉弓阿伐他汀水平为25 ng/g组织湿重。阿伐他汀使胸主动脉和髂股动脉的CE含量降低39%，胸主动脉病变范围降低41%，主动脉弓横截面积病变降低35%，单核细胞-巨噬细胞面积降低27%。单核细胞-巨噬细胞面积的减少反映了细胞数量的变化而非细胞大小的变化。在髂股动脉中，阿伐他汀使单核细胞-巨噬细胞含量降低77%，并使巨噬细胞与病变的比例从0.16降至0.05。在主动脉弓内，潜伏型和活性MMP-9的催化活性分别降低65%和33%；集体测定的潜伏型和活性MMP-1及MMP-3活性分别降低52%和60%，而MMP-2则无变化。主动脉弓MMP-9、基质金属蛋白酶组织抑制剂（TIMP）-1和TIMP-2的mRNA水平降低29%至39%，而MMP-2的mRNA水平升高。我们得出结论，生物可利用的ACAT抑制剂阿伐他汀可直接限制巨噬细胞积累，导致主要为纤维肌性病变的组织学表现，并可通过降低病变内MMP的表达潜在地稳定已形成的动脉粥样硬化病变。
