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.


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.


CONCLUSIONS
Our current findings uncover a novel mechanism by which AMPK protects against hypercholesterolemia-mediated endothelial dysfunction.
Li
Dan
D
Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong Province, 510080 People's Republic of China.
Zhang
Yuan
Y
Ma
Jing
J
Ling
Wenhua
W
Xia
Min
M
D020413:3' Untranslated Regions; D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000109:Acetylcholine / Q000494:pharmacology; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D002417:Cattle; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004789:Enzyme Activation; D020536:Enzyme Activators; D017930:Genes, Reporter; D006801:Humans; D006937:Hypercholesterolemia / Q000201:enzymology* / Q000503:physiopathology; D007653:Ketocholesterols / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D018384:Oxidative Stress; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D014162:Transfection; D015854:Up-Regulation; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D020413:3' Untranslated Regions; C419353:ABCG1 protein, human; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D020536:Enzyme Activators; D007653:Ketocholesterols; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D012265:Ribonucleotides; D014665:Vasodilator Agents; C516138:dorsomorphin; D009599:Nitroprusside; D009569:Nitric Oxide; D000620:Aminoimidazole Carboxamide; D052250:Nitric Oxide Synthase Type III; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D000109:Acetylcholine; C003001:7-ketocholesterol