title: AMP-activated protein kinase attenuates oxLDL uptake in macrophages through PP2A/NF-κB/LOX-1 pathway.
abstract: The differentiation of macrophages into lipid-laden foam cells is a hallmark in early-stage atherosclerosis. The developmental role of adenosine monophosphate-activated protein kinase (AMPK) in a transformation of foam cells, especially in macrophage cholesterol uptake that remains undetermined. Here we demonstrate that AMPK activation in response to IMM-H007 or AICAR resulted in a decrease in macrophage cholesterol uptake and thus inhibited foam cell formation in macrophages mediated by oxidized low-density lipoprotein (oxLDL). This functional change was caused by a downregulation of mRNA and protein expression of LOX-1 but not other scavenger receptors, including scavenger receptor-A (SR-A), CD36 and scavenger receptor-BI (SR-BI). The expression of LOX-1 was regulated by AMPK activation induced decreased phosphorylation of nuclear transcription factor NF-κB, since siRNA interference or dominant negative AMPK overexpression significantly promotes Ser536 dephosphorylation of NF-κB p65 and thus increases LOX-1 expression. Moreover, pharmacological AMPK activation was shown to promote protein phosphatase 2A (PP2A) activity and the specific PP2A inhibitor, okadaic acid, could prevent the effects of IMM-H007 or AICAR on NF-κB and LOX-1. In vivo, pharmacological AMPK activation reduced the lesion size of atherosclerosis and the expression of LOX-1 in aortas in apolipoprotein E-deficient mice. Our current findings suggest a novel mechanism of LOX-1 regulation by AMPK to attenuate macrophage oxLDL uptake and atherosclerosis.
authors: State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Nanwei Road A2, Beijing 100050, PR China; Beijing key laboratory of new drug mechanisms and pharmacological evaluation study, Nanwei Road A2, Beijing 100050, PR China; Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanwei Road A2, Beijing 100050, PR China.
authors: Bo
authors: B
authors: Chen
authors: State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Nanwei Road A2, Beijing 100050, PR China; Beijing key laboratory of new drug mechanisms and pharmacological evaluation study, Nanwei Road A2, Beijing 100050, PR China; Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanwei Road A2, Beijing 100050, PR China; Institute of Food Science and Technology CAAS, Chinese Academy of Agricultural Sciences, No. 1 Nongda South Rd., Beijing 100193, PR China.
authors: Jin
authors: J
authors: Li
authors: State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Nanwei Road A2, Beijing 100050, PR China; Beijing key laboratory of new drug mechanisms and pharmacological evaluation study, Nanwei Road A2, Beijing 100050, PR China; Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanwei Road A2, Beijing 100050, PR China. Electronic address: zhuhaibo@imm.ac.cn.
authors: Haibo
authors: H
authors: Zhu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism*; D004195:Disease Models, Animal; D005487:Foam Cells / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology; D054648:Protein Phosphatase 2 / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D051127:Scavenger Receptors, Class E / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D012265:Ribonucleotides; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; C000606090:triacetyl-3-hydroxyphenyladenosine; D019319:Okadaic Acid; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; D054648:Protein Phosphatase 2; C031143:AICA ribonucleotide; D000241:Adenosine
keywords: AICAR (PubChem CID: 17513); AMPK; Atherosclerosis; Compound C (PubChem CID: 11524144); LOX-1; Macrophage; Okadaic acid (PubChem CID: 446512); PDTC (PubChem CID: 2209); oxLDL uptake