Carvedilol inhibits tumor necrosis factor-alpha-induced endothelial transcription factor activation, adhesion molecule expression, and adhesiveness to human mononuclear cells.
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.
Chen
Jaw-Wen
JW
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
Lin
Feng-Yen
FY
Chen
Yung-Hsiang
YH
Wu
Tao-Cheng
TC
Chen
Yuh-Lien
YL
Lin
Shing-Jong
SJ
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
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