title: Activation of AMP-activated protein kinase is required for berberine-induced reduction of atherosclerosis in mice: the role of uncoupling protein 2.
abstract: OBJECTIVE
  Berberine, a botanical alkaloid purified from Coptidis rhizoma, is reported to activate the AMP-activated protein kinase (AMPK). Whether AMPK is required for the protective effects of berberine in cardiovascular diseases remains unknown. This study was designed to determine whether AMPK is required for berberine-induced reduction of oxidative stress and atherosclerosis in vivo.
  
  
  METHODS
  ApoE (ApoE⁻/⁻) mice and ApoE⁻/⁻/AMPK alpha 2⁻/⁻ mice that were fed Western diets were treated with berberine for 8 weeks. Atherosclerotic aortic lesions, expression of uncoupling protein 2 (UCP2), and markers of oxidative stress were evaluated in isolated aortas.
  
  
  RESULTS
  In ApoE⁻/⁻ mice, chronic administration of berberine significantly reduced aortic lesions, markedly reduced oxidative stress and expression of adhesion molecules in aorta, and significantly increased UCP2 levels. In contrast, in ApoE⁻/⁻/AMPK alpha 2⁻/⁻ mice, berberine had little effect on those endpoints. In cultured human umbilical vein endothelial cells (HUVECs), berberine significantly increased UCP2 mRNA and protein expression in an AMPK-dependent manner. Transfection of HUVECs with nuclear respiratory factor 1 (NRF1)-specific siRNA attenuated berberine-induced expression of UCP2, whereas transfection with control siRNA did not. Finally, berberine promoted mitochondrial biogenesis that contributed to up-regulation of UCP2 expression.
  
  
  CONCLUSIONS
  We conclude that berberine reduces oxidative stress and vascular inflammation, and suppresses atherogenesis via a mechanism that includes stimulation of AMPK-dependent UCP2 expression.
authors: Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.
authors: Qilong
authors: Q
authors: Wang
authors: Miao
authors: M
authors: Zhang
authors: Bin
authors: B
authors: Liang
authors: Najeeb
authors: N
authors: Shirwany
authors: Yi
authors: Y
authors: Zhu
authors: Ming-Hui
authors: MH
authors: Zou
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000737:chemistry / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D001599:Berberine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D058226:Plaque, Atherosclerotic / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D012694:Serine / Q000378:metabolism; D013912:Threonine / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014280:Triglycerides / Q000097:blood; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D000071246:Uncoupling Protein 2; D015854:Up-Regulation / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000447:Aldehydes; D001057:Apolipoproteins E; D001786:Blood Glucose; D007473:Ion Channels; D024101:Mitochondrial Proteins; D014280:Triglycerides; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D019010:Vascular Cell Adhesion Molecule-1; D001599:Berberine; D018799:Intercellular Adhesion Molecule-1; D013912:Threonine; C002744:3-nitrotyrosine; D014443:Tyrosine; D012694:Serine; D002784:Cholesterol; C534978:Prkaa2 protein, mouse; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; C027576:4-hydroxy-2-nonenal