title: AMP-activated protein kinase suppresses endothelial cell inflammation through phosphorylation of transcriptional coactivator p300.
abstract: OBJECTIVE
  Considerable evidence supports the early involvement of monocyte/macrophage recruitment to activated endothelial cells by leukocyte adhesion molecules during atherogenesis. AMP-activated protein kinase (AMPK) is highly expressed in vascular endothelial cells, but its impact on monocyte adhesion and the related mechanisms are not fully understood. The present study was designed to evaluate the impact of and gain mechanistic insight into the signaling coupling AMPK function to the antiinflammatory response.
  
  
  RESULTS
  5-Aminoimidazole-4-carboxamide-1-β-D-ribonucleotide (AICAR) treatment or overexpression of constitutively active AMPK markedly reduced human monocytic human acute monocytic leukemia cell line-1 cell adhesion and the expression of vascular cell adhesion molecule-1 in tumor necrosis factor-α-activated human aortic endothelial cells. Furthermore, AICAR or constitutively active AMPK overexpression strongly inhibited the histone acetyltransferase activity of the transcriptional coactivator p300 by phosphorylation of Ser89, which in turn decreased tumor necrosis factor-α-activated p300-mediated acetylation of nuclear factor-κB p65 on Lys221 and reduced the DNA binding activity of nuclear factor-κB by inhibiting its recruitment to its target gene promoters. AMPK phosphorylates the transcriptional coactivator p300 via the atypical protein kinase Cι/λ.
  
  
  CONCLUSIONS
  Our findings demonstrate that transcriptional coactivator p300 phosphorylation at Ser89 by AMPK is critical for the therapeutic effect of AMPK and may be a potential target for pharmaceutical intervention in inflammatory diseases such as atherosclerosis.
authors.affiliation: Department of Cardiovascular Medicine, General Hospital of Guangzhou Military Command, Guangzhou, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Qiu
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wang
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Xia
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D001011:Aorta / Q000166:cytology; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control*; D009000:Monocytes / Q000166:cytology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D012265:Ribonucleotides; D019010:Vascular Cell Adhesion Molecule-1; D000620:Aminoimidazole Carboxamide; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D051548:Histone Acetyltransferases; D011493:Protein Kinase C; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide