Effects of nebivolol on proliferation and apoptosis of human coronary artery smooth muscle and endothelial cells.

Abstract

Secondary failure due to late restenosis continues to occur in 30-50% of individuals after PTCA. beta-Blockers play an important role in the treatment of CAD. The aim of this study was to investigate the effects of the new beta-blocker nebivolol on cell proliferation of human coronary smooth muscle cells (haCSMCs) and endothelial cells (haECs) in comparison to traditional beta-blockers. The effect of nebivolol and other beta-blockers on proliferation of HaECs and HaCSMCs was analyzed by bromodeoxyuridine incorporation. Apoptosis was measured by determination of hypodiploid DNA in both cell types. Additionally, in HaECs NO formation, endothelin-1 transcription and secretion were determined. Incubation for 1, 2, 4, 7 or 14 days resulted in a concentration- and time-dependent reduction of proliferation up to 80% in HaECs and HaCSMCs. beta-Blockers such as propranolol, metoprolol or bisoprolol did not exert this effect. Nebivolol inhibited accelerated haCSMC proliferation even in the presence of growth factors such as TGFbeta(1) and PDGF-BB. Nebivolol concentration-dependently induced a moderate apoptosis (10(-5) mol/l: 23%) and a decrease of haCSMCs in the S-phase by 66%. HaECs showed comparable results. During nebivolol incubation NO formation of HaCEs increased, while endothelin-1 transcription and secretion were suppressed. Whereas classical beta-blockers do not affect cell growth, only nebivolol inhibits haCSMC or haEC proliferation and induces a moderate rate of apoptosis. Furthermore, in HaCEs NO formation increases and endothelin-1 secretion decreases suggesting that nebivolol may represent a beta-blocker with great promises in CAD therapy.