title: Troglitazone does not initiate hypertrophy but can sensitise cardiomyocytes to growth effects of serum.
abstract: Chronic administration of troglitazone might predispose to cardiac hypertrophy. The aims of the study were to determine if troglitazone could (i) initiate a trophic response directly in ventricular cardiomyocytes and (ii) modify responses to other trophic stimuli. After 24 h, troglitazone (10 nM-10 microM) (i) did not increase cellular protein mass and decreased incorporation of [14C]phenylalanine, a marker of protein synthesis, (ii) interacted with serum (10% v/v) and insulin-like growth factor-1 (10 nM) to produce small trophic responses, (iii) increased cellular protein mass but not protein synthesis with insulin (1 unit/ml). Troglitazone (1 microM) attenuated responses to phorbol-12-myristate-13-acetate (PMA) (100 nM), and noradrenaline (5 microM) and endothelin-1 (100 nM), which also activate protein kinase C. In summary, troglitazone does not initiate cardiomyocyte growth directly in vitro, and can inhibit protein kinase C-mediated growth mechanisms. However, the interaction of troglitazone with serum growth factors may contribute modestly to the development of hypertrophy. As troglitazone produced a moderate hypertrophic effect per se in re-differentiated cardiomyocytes, it may directly increase the severity of established hypertrophy.
authors.affiliation: Department of Therapeutics and Pharmacology, Centre for Cardiovascular Research, School of Medicine, The Queen's University of Belfast, Whitla Medical Building, 97 Lisburn Road, Belfast, UK. d.bell@qub.ac.uk
authors.forename: D
authors.initials: D
authors.lastname: Bell
authors.forename: B J
authors.initials: BJ
authors.lastname: McDermott
mesh_terms: D000818:Animals; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000009:adverse effects / Q000494:pharmacology*; D003470:Culture Media / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019332:Endothelin-1 / Q000494:pharmacology; D005312:Fetal Blood; D005947:Glucose / Q000494:pharmacology; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D006984:Hypertrophy / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009638:Norepinephrine / Q000494:pharmacology; D010649:Phenylalanine / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013844:Thiazoles / Q000009:adverse effects / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone
chemical_list: D002839:Chromans; D003470:Culture Media; D019332:Endothelin-1; D007004:Hypoglycemic Agents; D007328:Insulin; D013844:Thiazoles; D045162:Thiazolidinediones; D010649:Phenylalanine; D007334:Insulin-Like Growth Factor I; D011493:Protein Kinase C; D000077288:Troglitazone; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate; D009638:Norepinephrine