Adenosine Monophosphate Activated Protein Kinase Regulates ABCG1-Mediated Oxysterol Efflux From Endothelial Cells and Protects Against Hypercholesterolemia-Induced Endothelial Dysfunction

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 (LXRα) 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-β-d-riboside treatment promotes endothelial 7-ketocholesterol efflux and prevents 7-ketocholesterol (7-KC)–induced reactive...