Adenosine Monophosphate Activated Protein Kinase Regulates ABCG1-Mediated Oxysterol Efflux From Endothelial Cells and Protects Against Hypercholesterolemia-Induced Endothelial Dysfunction
Adenosine Monophosphate Activated Protein Kinase Regulates ABCG1-Mediated Oxysterol Efflux From Endothelial Cells and Protects Against Hypercholesterolemia-Induced Endothelial Dysfunction
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DOI：
10.1161/atvbaha.110.204230
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发表时间：
2010-07-01
影响因子：
8.7
通讯作者：
Xia, Min
中科院分区：
文献类型：
--
作者：
Li, Dan;Zhang, Yuan;Xia, Min
目的：腺苷单磷酸活化蛋白激酶（AMPK）已被确定为通过保存内皮细胞（EC）功能来调节血管功能。在这项研究中，我们研究了AMPK对内皮细胞的有益作用是否依赖于其参与胆固醇外排及其对高胆固醇血症诱导的内皮功能障碍的影响。方法和结果：通过人主动脉内皮细胞和牛主动脉内皮细胞，我们发现AMPK激活上调ATP结合盒G1 （ABCG1）的表达，而不依赖于肝X受体α (LXR α)的转录活性，但通过转录后机制增加mRNA的稳定性。利用异种系统和荧光素酶报告基因，我们进一步确定ABCG1 mRNA的3'-非翻译区负责AMPK激活的调控作用。5-氨基咪唑-4-羧酰胺-1- β -d -核苷处理促进内皮细胞7-酮胆固醇外溢，并以abcg1依赖的方式阻止7-酮胆固醇（7-KC）诱导的活性氧产生，从而保持内皮细胞一氧化氮合酶活性和一氧化氮的生物利用度。值得注意的是，接受高胆固醇饮食的C57BL/6J小鼠的体内研究显示，输注5-氨基咪唑-4-羧酰胺-1- β - d -核糖体可增加血管ABCG1的表达并改善血管反应性。这些作用被AMPK拮抗剂化合物C和ABCG1小干扰RNA的血管基因转移所消除。结论：我们目前的发现揭示了AMPK防止高胆固醇血症介导的内皮功能障碍的新机制。（中华动脉血管杂志，2010;30:1354-1362）
Objective-Adenosine monophosphate activated protein kinase (AMPK) has been identified as a regulator of vascular function via the preservation of endothelial cell (EC) function. In this study, we examined whether the beneficial effects of AMPK on ECs are dependent on its involvement in cholesterol efflux and its impact on hypercholesterolemia-induced endothelial dysfunction.Methods and Results-Using human aortic ECs and bovine aortic ECs, we show that AMPK activation upregulates ATP binding cassette G1 (ABCG1) expression independently of liver X receptor alpha (LXR alpha) transcriptional activity but through a posttranscriptional mechanism that increases mRNA stability. Using a heterologous system and a luciferase reporter, we further identify that the 3'-untranslated region of the ABCG1 mRNA is responsible for the regulatory effects of AMPK activation. 5-Aminoimidazole-4-carboxamide-1-beta-D-riboside treatment promotes endothelial 7-ketocholesterol efflux and prevents 7-ketocholesterol (7-KC)-induced reactive oxygen species production in an ABCG1-dependent manner, thus preserving endothelial nitric oxide synthase activity and nitric oxide bioavailability. Notably, in vivo studies using C57BL/6J mice receiving a high-cholesterol diet revealed that the infusion of 5-aminoimidazole-4-carboxamide-1-beta-D-riboside increases vascular ABCG1 expression and improves vascular reactivity. These effects are abrogated by the AMPK antagonist compound C and by the vascular gene transfer of ABCG1 small interfering RNA.Conclusion-Our current findings uncover a novel mechanism by which AMPK protects against hypercholesterolemia-mediated endothelial dysfunction. (Arterioscler Thromb Vasc Biol. 2010; 30: 1354-1362.)