INHIBITION OF ACYL-COA CHOLESTEROL O-ACYLTRANSFERASE REDUCES THE CHOLESTERYL ESTER ENRICHMENT OF ATHEROSCLEROTIC LESIONS IN THE YUCATAN MICROPIG
INHIBITION OF ACYL-COA CHOLESTEROL O-ACYLTRANSFERASE REDUCES THE CHOLESTERYL ESTER ENRICHMENT OF ATHEROSCLEROTIC LESIONS IN THE YUCATAN MICROPIG
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DOI：
10.1016/0021-9150(93)90020-u
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发表时间：
1993-03-01
期刊：
影响因子：
5.3
通讯作者：
BLACK, AE
中科院分区：
文献类型：
--
作者：
BOCAN, TMA;MUELLER, SB;BLACK, AE
动脉粥样硬化病变的发展可以通过调节血浆胆固醇间接改变，或通过抑制动脉细胞内的酰基辅酶A胆固醇O-酰基转移酶（ACAT）直接改变。尤卡坦小型猪喂食2%胆固醇、8%花生油、8%椰子油纯化饲料1个月，然后给予有效的、生物可利用的ACAT抑制剂CI-976，并通过慢性内皮损伤诱导动脉粥样硬化病变。治疗84-108天后，CI-976使平均血浆VLDL-胆固醇降低85-91%，累积VLDL-暴露（VLDL-时间曲线下面积）降低65%。然而，总体血浆总胆固醇、LDL和HDL胆固醇以及甘油三酯水平无变化。CI-976使肝脏胆固醇酯（CE）含量降低65%，而对肾上腺CE含量无显著影响。通过CI-976，受损左股动脉、左髂动脉和腹主动脉以及未受损右股动脉、髂动脉和胸主动脉的CE含量降低62-78%。给药后24小时测量的全身血浆CI-976水平范围为2.26 - 4.05 μ g/ml，与VLDL和血管CE含量的降低显著相关。因此，我们得出结论，ACAT的抑制可以钝化胆固醇酯富集的发展动脉粥样硬化病变，通过防止再酯化和储存的脂蛋白胆固醇在血管细胞内，并通过降低血浆水平和输送到动脉壁的致动脉粥样硬化脂蛋白VLDL。
Atherosclerotic lesion development may be altered indirectly by regulating plasma cholesterol or directly by inhibition of acyl-CoA cholesterol O-acyltransferase (ACAT) within cells of the artery. Yucatan micropigs were meal-fed a 2% cholesterol, 8% peanut oil, 8% coconut oil purified diet for 1 month prior to administration of the potent, bioavailable ACAT inhibitor CI-976, and induction of atherosclerotic lesions by chronic endothelial damage. After 84-108 days of therapy, CI-976 decreased mean plasma VLDL-cholesterol 85-91% and cumulative VLDL-exposure (area under VLDL-time curve) by 65%. However, overall plasma total, LDL and HDL cholesterol and triglyreride levels were unchanged. CI-976 decreased liver cholesteryl ester (CE) content 65% without significantly affecting adrenal CE content. The CE content of the injured left femoral, left iliac and abdominal aorta and uninjured right femoral and iliac arteries and thoracic aorta was reduced 62-78% by CI-976. Systemic plasma CI-976 levels measured 24 h post-dose ranged from 2.26 to 4.05 mug/ml and significantly correlated with the reduction in both VLDL and vessel CE content. Thus, we conclude that inhibition of ACAT can blunt the cholesteryl ester enrichment of developing atherosclerotic lesions by preventing reesterification and storage of lipoprotein cholesterol within vascular cells and by reducing the plasma level and delivery to the arterial wall of such atherogenic lipoproteins as VLDL.