on September 16, 2004
Published online before print September 16, 2004, doi: 10.1161/01.ATV.0000145016.69181.fa
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Submitted on March 20, 2004
Accepted on August 11, 2004
Carvedilol Inhibits Tumor Necrosis Factor-
-Induced Endothelial Transcription Factor Activation, Adhesion Molecule Expression, and Adhesiveness to Human Mononuclear Cells
Jaw-Wen Chen *;
From the National Yang-Ming University School of Medicine (J.-W.C., Y.-H.C., T.-C.W., Y.-L.C., S.-J.L.), Cardiovascular Research Center; the Division of Cardiology (J.-W.C., T.-C.W., S.-J.L.), Department of Medicine, Taipei Veterans General Hospital; and the Graduate Institute of Medical Science (F.-Y.L.), National Defense Medical Center, Taipei, Taiwan, Republic of China.
* To whom correspondence should be addressed. E-mail: jwchen{at}vghtpe.gov.tw.
Objective--We tested the hypothesis that carvedilol, a 
-adrenoceptor and 
-adrenoceptor antagonist with potent antioxidant property, could inhibit tumor necrosis factor- (TNF-)-induced endothelial adhesiveness to human mononuclear cells (MNCs), an early sign of atherogenesis.
Methods and Results--Circulating MNCs were isolated from the peripheral blood of healthy subjects. Compared with control condition, pretreatment of carvedilol (10 µmol/L for 18 hours) or probucol (5 µmol/L for 18 hours), but not propanolol, prazosin, or both propanolol and prazosin significantly decreased TNF--stimulated adhesiveness of cultured human aortic endothelial cells (HAECs) to MNCs. Carvedilol inhibited TNF--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--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--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.
Key words: antioxidant • atherosclerosis • carvedilol • cell adhesion molecules • endothelium
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