The ACAT inhibitor avasimibe reduces macrophages and matrix metalloproteinase expression in atherosclerotic lesions of hypercholesterolemic rabbits
The ACAT inhibitor avasimibe reduces macrophages and matrix metalloproteinase expression in atherosclerotic lesions of hypercholesterolemic rabbits
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DOI：
10.1161/01.atv.20.1.70
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发表时间：
2000-01-01
影响因子：
8.7
通讯作者：
Lee, H
中科院分区：
文献类型：
--
作者：
Bocan, TMA;Krause, BR;Lee, H
考虑到胆固醇酯（CE）积累在巨噬细胞泡沫细胞形成中的重要性，我们假设酰基辅酶A：胆固醇O-酰基转移酶（ACAT）抑制剂将通过限制巨噬细胞富集产生组织学稳定的病变，从而成为基质金属蛋白酶（MMP）的来源。雄性新西兰白色兔连续喂食胆固醇/脂肪饲料9周，仅喂食脂肪饲料6周，并喂食25 mg/kg阿伐麦贝7至8周。Avasimibe对血浆总胆固醇暴露量无影响。血浆阿伐司米贝最大浓度和24小时曲线下面积水平分别为178 ng/mL和2525 ng。h/mL。当在不存在白蛋白的情况下测定时，对人单核细胞-巨噬细胞ACAT的中位抑制浓度为12 ng/mL，主动脉弓阿伐司米贝水平为25 ng/g组织湿重。Avasimibe使胸主动脉和髂股动脉CE含量降低39%，胸主动脉病变程度降低41%，主动脉弓横截面病变面积降低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而不是细胞大小的变化。在髂股动脉中，avasimibe使单核细胞-巨噬细胞含量降低了77%，并使巨噬细胞与病变的比率从0.16降至0.05。在主动脉弓内，潜伏和活性MMP-9的催化活性分别降低了65%和33%;共同测量的潜伏和活性MMP-1和MMP-3活性分别降低了52%和60%，MMP-2没有变化。主动脉弓MMP-9、基质金属蛋白酶组织抑制剂（TIMP）-1和TIMP-2 mRNA水平降低29%至39%，MMP-2 mRNA水平升高。我们的结论是，生物可利用的ACAT抑制剂阿伐麦贝可以直接限制巨噬细胞的积累，导致主要的纤维肌病变的组织学外观，并可能通过减少病变内MMP的表达来稳定预先建立的动脉粥样硬化病变。
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.