Troglitazone does not initiate hypertrophy but can sensitise cardiomyocytes to growth effects of serum.
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.
Bell
D
D
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
McDermott
B J
BJ
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
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