© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Carvedilol prevents epinephrine-induced apoptosis in human coronary artery endothelial cells*
modulation of Fas/Fas ligand and caspase-3 pathway
aDepartment of Cardiology, Second University, Rome, Italy
bDepartments of Medicine and Physiology, University of Florida College of Medicine and VA Medical Center, 1600 Archer Rd., P.O. Box 100277 JHMHC, Gainesville, FL 32610, USA
* Corresponding author. Tel.: +1-352-370-4160; fax: +1-352-379-4161 mehta{at}medmac.ufl.edu
Background: Several studies have shown that carvedilol, a multiple action neurohumoral antagonist, reduces mortality in patients with congestive heart failure (CHF). In addition to being a β-adrenoceptor antagonist, carvedilol is a potent antioxidant. Since there is evidence for elevation of catecholamine levels in plasma and coronary artery endothelial cell injury in CHF, the present study was designed to test the hypothesis that carvedilol inhibits epinephrine-induced apoptosis, and the inhibitory effect is mediated by modulation of Fas, Fas ligand (FasL) and caspase-3 pathway, in cultured human coronary artery endothelial cells (HCAECs). Methods and results: HCAECs were exposed to epinephrine alone, carvedilol+epinephrine, or atenolol+epinephrine for 24 h. Epinephrine increased the number of apoptotic cells, measured by in situ nick end-labeling staining (from 4.2±1.3% to 28.6±6.0%, P<0.01, n=6) and by DNA laddering on agarose gel electrophoresis. Epinephrine also increased Fas and FasL protein expression (P<0.01 vs. control, n=6), and activated intracellular protease caspase-3 (P<0.01 vs. control, n=6). These effects of epinephrine were completely inhibited by carvedilol. Atenolol in equimolar concentration also attenuated epinephrine-mediated effects, but the effects of atenolol were less marked than those of carvedilol (P<0.01). To explore the basis of differential effects of carvedilol and atenolol, effects of these agents on epinephrine-induced lipid peroxidation was measured. Lipid peroxidation was completely blocked by carvedilol, whereas equimolar concentration of atenolol had much less (P<0.05) effect. Conclusion: Epinephrine induces apoptosis in HCAECs, and this effect is associated with activation of Fas–FasL and caspase-3 signal transduction pathway. Carvedilol can, more effectively than atenolol, inhibit these effects of epinephrine. The potent antioxidant effect of carvedilol is probably responsible for the superior effect.
KEYWORDS Adrenergic (ant)agonists; Apoptosis; Endothelial function; Free radicals
* Supported by a Merit Review Award from the VA Central Office and funds from Smith Kline Beecham, Philadelphia, PA, USA.
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