Rimonabant is a dual inhibitor of acyl CoA:cholesterol acyltransferases 1 and 2.
Rimonabant is a dual inhibitor of acyl CoA:cholesterol acyltransferases 1 and 2.
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DOI：
10.1016/j.bbrc.2010.06.134
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发表时间：
2010-08-06
影响因子：
3.1
通讯作者：
Thewke, Douglas P.
中科院分区：
文献类型：
--
作者：
Netherland, Courtney;Thewke, Douglas P.
关键词：
酰基辅酶A：胆固醇酰基转移酶（ACAT）催化胆固醇酯（CE）的细胞内合成。ACAT亚型ACAT 1和ACAT 2在动脉粥样硬化的病理生理学中起关键作用，并且ACAT抑制剂在动物模型中延缓动脉粥样硬化。利莫那班是一种1型大麻素受体（CB 1）拮抗剂，通过尚不完全清楚的机制在人类和动物中产生抗动脉粥样硬化作用。利莫那班在结构上类似于另外两种大麻素受体拮抗剂，AM 251和SR 144528，最近被确定为ACAT的有效抑制剂。因此，我们使用体内基于细胞的测定和体外无细胞测定来检查利莫那班对ACAT的影响。利莫那班剂量依赖性地降低Raw 264.7巨噬细胞（IC 50 = 2.9 ± 0.38 µM）和分离的腹膜巨噬细胞中的ACAT活性。利莫那班抑制完整CHO-ACAT 1和CHO-ACAT 2细胞中的ACAT活性和无细胞试验中的ACAT活性的效率大致相同（CHO-ACAT 1和CHO-ACAT 2的IC 50分别为1.5 ± 1.2 µM和2.2 ± 1.1 µM）。与ACAT抑制一致，利莫那班治疗阻断了巨噬细胞中的ACAT依赖性过程、氧化固醇诱导的细胞凋亡和乙酰化LDL诱导的泡沫细胞形成。从这些结果中，我们得出结论，利莫那班是一种ACAT 1/2双重抑制剂，并表明利莫那班的一些动脉粥样硬化有益作用，至少部分是由于抑制ACAT。
Acyl-coenzymeA:cholesterol acyltransferase (ACAT) catalyzes the intracellular synthesis of cholesteryl esters (CE). Both ACAT isoforms, ACAT1 and ACAT2, play key roles in the pathophysiology of atherosclerosis and ACAT inhibition retards atherosclerosis in animal models. Rimonabant, a type 1 cannabinoid receptor (CB1) antagonist, produces anti-atherosclerotic effects in humans and animals by mechanisms which are not completely understood. Rimonabant is structurally similar to two other cannabinoid receptor antagonists, AM251 and SR144528, recently identified as potent inhibitors of ACAT. Therefore, we examined the effects of Rimonabant on ACAT using both in vivo cell-based assays and in vitro cell-free assays. Rimonabant dose-dependently reduced ACAT activity in Raw 264.7 macrophages (IC50= 2.9 ± 0.38 µM) and isolated peritoneal macrophages. Rimonabant inhibited ACAT activity in intact CHO-ACAT1 and CHO-ACAT2 cells and in cell-free assays with approximately equal efficiency (IC50=1.5 ± 1.2 µM and 2.2 ± 1.1 µM for CHO-ACAT1 and CHO-ACAT2, respectively). Consistent with ACAT inhibition, Rimonabant treatment blocked ACAT-dependent processes in macrophages, oxysterol-induced apoptosis and acetylated-LDL induced foam cell formation. From these results we conclude that Rimonabant is an ACAT1/2 dual inhibitor and suggest that some of the atherosclerotic beneficial effects of Rimonabant are, at least partly, due to inhibition of ACAT.
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影响因子：
6.5
作者：
Freeman-Anderson, Natalie E.;Pickle, Theresa G.;Thewke, Douglas P.
通讯作者：
Thewke, Douglas P.
DOI：
10.1161/atvbaha.107.147405
发表时间：
2007-11-01
影响因子：
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168.9
作者：
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8.7
作者：
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通讯作者：
Wee, SB
影响因子：
64.8
作者：
MUNRO, S;THOMAS, KL;ABUSHAAR, M
通讯作者：
ABUSHAAR, M