title: Carvedilol inhibits tumor necrosis factor-alpha-induced endothelial transcription factor activation, adhesion molecule expression, and adhesiveness to human mononuclear cells.
abstract: OBJECTIVE
  We tested the hypothesis that carvedilol, a beta-adrenoceptor and alpha-adrenoceptor antagonist with potent antioxidant property, could inhibit tumor necrosis factor-alpha (TNF-alpha)-induced endothelial adhesiveness to human mononuclear cells (MNCs), an early sign of atherogenesis.
  
  
  RESULTS
  Circulating MNCs were isolated from the peripheral blood of healthy subjects. Compared with control condition, pretreatment of carvedilol (10 micromol/L for 18 hours) or probucol (5 micromol/L for 18 hours), but not propanolol, prazosin, or both propanolol and prazosin significantly decreased TNF-alpha-stimulated adhesiveness of cultured human aortic endothelial cells (HAECs) to MNCs. Carvedilol inhibited TNF-alpha-stimulated endothelial vascular cell adhesion molecule-1 (VCAM-1) and E-selectin (66.0+/-2.0% and 55.60+/-1.0% of control, P<0.05, respectively) expression, whereas probucol inhibited only VCAM-1 expression (79.0+/-5.0% of control, P<0.05). Propanolol, prazosin, or both did not alter the expression of adhesion molecules. Further, pretreatment with carvedilol significantly inhibited TNF-alpha-stimulated intracellular reactive oxygen species (ROS) production and the activation of redox sensitive nuclear factor kappa B and activator protein-1 transcription pathways.
  
  
  CONCLUSIONS
  Carvedilol reduced TNF-alpha-stimulated endothelial adhesiveness to human MNCs by inhibiting intracellular ROS production, transcription factor activation, and VCAM-1 as well as E-selectin expression, suggesting its potential role in clinical atherosclerosis disease.
authors.affiliation: National Yang-Ming University School of Medicine, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, 201, Sec 2, Shih-Pai Road, Taipei, Taiwan 112, Republic of China. jwchen@vghtpe.gov.tw
authors.forename: Jaw-Wen
authors.initials: JW
authors.lastname: Chen
authors.forename: Feng-Yen
authors.initials: FY
authors.lastname: Lin
authors.forename: Yung-Hsiang
authors.initials: YH
authors.lastname: Chen
authors.forename: Tao-Cheng
authors.initials: TC
authors.lastname: Wu
authors.forename: Yuh-Lien
authors.initials: YL
authors.lastname: Chen
authors.forename: Shing-Jong
authors.initials: SJ
authors.lastname: Lin
mesh_terms: D001011:Aorta; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019040:E-Selectin / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000737:chemistry* / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D002227:Carbazoles; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D016328:NF-kappa B; D011412:Propanolamines; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D000077261:Carvedilol; D018799:Intercellular Adhesion Molecule-1