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-HT(2B) receptor blocker (SB-204741) and GSK-3β 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-β/NF-κB/TNF-α and CRP), and apoptotic markers (TUNEL positivity and Bax expression) along with phosphorylation of Akt/GSK-3β/β-catenin/eNOS. Intriguingly, co-treatment with GSK-3β 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-HT(2B) receptor blockade mediated anti-hypertrophic effect is atleast in part is governed through phosphorylation of Akt/GSK-3β/β-catenin/eNOS via attenuating inflammatory and apoptotic pathways.
Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110 029, India.
Saurabh
S
Bharti
Ratnakar
R
Singh
S S
SS
Chauhan
Tajamul
T
Hussain
Omar S
OS
Al-Attas
Dharamvir Singh
DS
Arya
D000818:Animals; D006332:Cardiomegaly / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D007211:Indoles / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism / Q000502:physiology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013876:Thiophenes / Q000494:pharmacology
D007211:Indoles; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D044403:Receptor, Serotonin, 5-HT2B; C417521:SB 216763; D058830:Serotonin 5-HT2 Receptor Antagonists; D013876:Thiophenes; C055058:5-(3-hydroxybenzoyl)-2-thiophenesulfonamide; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D007545:Isoproterenol