Effects of rosiglitazone and interactions with growth-regulating factors in ventricular cell hypertrophy.
Chronic administration of thiazolidinediones might predispose to cardiac hypertrophy. The aim was to investigate direct effects of rosiglitazone in rat ventricular cardiomyocytes maintained in vitro (24 h). Rosiglitazone (< or =10(-5) M) did not increase protein synthesis and produced small inconsistent increases in cellular protein. In the presence of serum (10% v/v), but not insulin-like growth factor (IGF-1, 10(-8) M) or insulin (1 U/ml), an interaction with rosiglitazone to stimulate protein synthesis was observed. The hypertrophic responses to noradrenaline (5x10(-6) M), PMA (10(-7) M) and ET-1 (10(-7) M) were not attenuated by rosiglitazone. Rosiglitazone (10(-7) M) did not influence protein synthesis in response to insulin (1 U/ml) and elevated glucose (2.5x10(-2) M) alone or in combination, but attenuated the increase in protein mass observed in response to elevated glucose alone. In re-differentiated cardiomyocytes, a model of established hypertrophy, rosiglitazone (10(-8) M-10(-6) M) increased protein synthesis. Together, these data indicate that rosiglitazone does not initiate cardiomyocyte hypertrophy directly in vitro. However, during chronic administration, the interaction of rosiglitazone with locally-derived growth-regulating factors may make a modest contribution to cardiac remodelling and influence the extent of compensatory hypertrophy of the compromised rat heart.
Bell
David
D
Department of Therapeutics and Pharmacology, Cardioendocrine Research Group, Centre for Cardiovascular Research, The School of Medicine, The Queen's University of Belfast, Northern Ireland, UK. d.bell@qub.ac.uk
McDermott
Barbara J
BJ
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003470:Culture Media / Q000494:pharmacology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019332:Endothelin-1 / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006984:Hypertrophy; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009638:Norepinephrine / Q000494:pharmacology; D010649:Phenylalanine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology*
D003470:Culture Media; D016895:Culture Media, Serum-Free; D019332:Endothelin-1; D007328:Insulin; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D010649:Phenylalanine; D007334:Insulin-Like Growth Factor I; D005947:Glucose; D007545:Isoproterenol; D013755:Tetradecanoylphorbol Acetate; D009638:Norepinephrine