Phosphorylation of Akt/GSK-3β/eNOS amplifies 5-HT2B receptor blockade mediated anti-hypertrophic effect in rats

Herein, we studied the cross talk between 5-HT2B receptor blocker (SB-204741) and GSK-3 beta inhibitor (SB-216763) in isoproterenol-induced cardiac hypertrophy for 28 days. SB-204741 treatment significantly ameliorated (P < 0.05) myocardial dysfunction, myocyte area, fibrosis and myocardial architecture in isoproterenol insulted myocardium. Moreover, this improvement in functional and morphological changes was associated with suppression of hypertrophic (BNP and CK-MB), inflammatory (IKK-beta/NF-kappa B/TNF-alpha and CRP), and apoptotic markers (TUNEL positivity and Bax expression) along with phosphorylation of Akt/GSK-3 beta/beta-catenin/eNOS. Intriguingly, co-treatment with GSK-3 beta inhibitor (P < 0.01) further amplified the anti-hypertrophic effect of SB-204741 (P < 0.05) such that the effect was indistinguishable from that of vehicle treated rats. Thus, 5-HT2B receptor blockade mediated anti-hypertrophic effect is atleast in part is governed through phosphorylation of Akt/GSK-3 beta/beta-catenin/eNOS via attenuating inflammatory and apoptotic pathways. (C) 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.