Nebivolol inhibits human aortic smooth muscle cell growth:: Effects on cell cycle regulatory proteins

An enhanced vasoconstriction and vascular smooth muscle cell proliferation are involved in pathogenesis of hypertension. beta-Blockers are effective for treatment of hypertensive patients. Recently the new beta(1)-receptor blocker nebivolol showed a different hemodynamic profile from those of other classic beta-blockers. In this study we hypothesized that nebivolol may also have different effects on smooth muscle cell proliferation compared with other beta-brockers such as atenolol. Human aortic smooth muscle cells (SMCs) were cultured, and cell growth was determined by increase in cell number. Growth-signaling molecules such as mitogen-activated protein kinase (p42(mapk)) and S6-kinase (p70(S6K)) and cell-cycle regulatory proteins (i.e., Cdk2, p27(KipI), and pRb) were analyzed by immunoblotting. In cultured human aortic SMCs, cell number was markedly increased in response to 5% fetal calf serum (FCS) over 6 days (87 +/- 11 x 10(3)/well), which was inhibited by nebivolol (10(-8)-10(-5) M; 25 +/- 2 x 10(3)/well; n = 6; p < 0.05), but not by atenolol. 5% FCS activated p42(mapk), S6K, and Cdk2, but downregulated F27(Kip1) and hyperphosphorylated pRb. Nebivolol prevented Cdk2 activation without influencing p42(mapk), S6K, pRB, and p27(Kip1). Thus, the new beta(1)-blocker nebivolol exhibits antiproliferative effect on human SMC through inactivation of Cdk2. This effect of nebivolol may have advantages over other beta-blockers in treatment of patients with cardiovascular disease.