title: AMPK activation reduces the number of atheromata macrophages in ApoE deficient mice.
abstract: CC chemokine receptor 2 (Ccr2) governs migration of inflammatory Ly6Chimonocytes from the bone marrow (BM) to the circulating blood, which is a key step for macrophage accumulation during progression of atherosclerosis. Hyperlipidemia is often accompanied by low AMP-activated kinase (AMPK) activity and increased expression of Ccr2. The aim of this study was to examine whether there is a link between AMPK and chemokine networks.
  
  
  
  ApoE-/-mice were fed a western diet and treated daily with AMPK activators (AICAR, A769662, or Metformin) or vehicle for 10 weeks. The effect of AMPK activators on pro-inflammatory myeloid cell numbers within the BM, blood, spleen, and aorta of ApoE-/-mice was then examined.
  
  
  
  We found that AMPK activation significantly reduced the number of Ly6Chimonocytes in the blood and atherosclerotic plaques. This reduction was caused by down-regulation of Ccr2 protein expression, which inhibited Ccr2-mediated migration of Ly6Chimonocytes from the BM to the circulation. There was no effect on proliferation or apoptosis of BM-derived Ly6Chimonocytes. AMPK activation caused Ly6Chimonocytes to accumulate in the BM, with a concomitant reduction in numbers in the blood and spleen.
  
  
  
  AMPK activation reduces the formation of atheromata-inducing macrophages in ApoE-/--deficient mice by inhibiting expression of Ccr2, thereby preventing the Ccr2-mediated migration of Ly6Chimonocytes from the BM. Therefore, AMPK may be a promising target for the treatment of atherosclerosis.
authors.affiliation: State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, China; Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, 030006, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, China.
authors.forename: Ang
authors.initials: A
authors.lastname: Ma
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, USA. Electronic address: m-zhao@northwestern.edu.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, China. Electronic address: zhuhaibo@imm.ac.cn.
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D001018:Aortic Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D001713:Biphenyl Compounds; D002460:Cell Line; D002464:Cell Migration Inhibition; D002633:Chemotaxis / Q000187:drug effects*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology; D008687:Metformin / Q000494:pharmacology; D018345:Mice, Knockout; D010641:Phenotype; D011753:Pyrones / Q000494:pharmacology; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D000950:Antigens, Ly; D001057:Apolipoproteins E; D001713:Biphenyl Compounds; C515335:Ccr2 protein, mouse; D020536:Enzyme Activators; C494192:Ly-6C antigen, mouse; D011753:Pyrones; D054390:Receptors, CCR2; D012265:Ribonucleotides; D013876:Thiophenes; D000620:Aminoimidazole Carboxamide; D008687:Metformin; C548179:Prkaa1 protein, mouse; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile
keywords: AMPK; Atherosclerosis; Ccr2; Ly6C(hi); Migration; Monocyte