SB-271258, A major metabolite in the dog of the thiazolidinedione, rosiglitazone, stimulates protein synthesis in re-differentiated rat cardiomyocytes in vitro

Abstract

In dogs, chronic administration of thiazolidinediones causes cardiac hypertrophy in vivo at high doses. The hypertrophic action of rosiglitazone in dogs might be attributed to production of SB-271258 (a major metabolite in dogs but minor in rats and man), rather than a direct effect on myocardium. The hypothesis that SB-271258 had potential to initiate cardiomyocyte hypertrophy or to modify responses elicited by other hypertrophic stimuli was tested in an in vitro bioassay utilising adult rat ventricular cardiomyocytes. SB-271258 increased protein and incorporation of 14C-phenylalanine, a marker of protein synthesis, in rat cardiomyocytes maintained in serum-free culture (24 h), maximally at 1 μM by 15.0% and 9.1%, respectively. In the presence of serum (10% v/v), SB-271258 elicited a moderate trophic effect: cellular protein and incorporation of 14C-phenylalanine were increased, maximally at 100 nM by 31.7% and 36.3%, respectively, above basal values (18.6% and 13.3% increases above serum response). In the presence of IGF-1 (10 nM) plus SB-271258, protein synthesis was increased, maximally by 45.5% above basal value (increase of 6.9% above IGF-1 alone). In contrast, SB-271258 attenuated the increase (12.0%) in cellular protein elicited by IGF-1. In re-differentiated cardiomyocytes, a model of relevance to established hypertrophy, SB-271258 (1 nM–1 μM) elicited a marked trophic effect per se, as evidenced by the maximum increase (at 100 nM), in protein synthesis of 24.5%. In conclusion, these data imply that cardiac hypertrophy associated with chronic administration of rosiglitazone in dogs in previous in vivo studies might be partly attributable to production of the metabolite SB-271258 since this metabolite was shown to elicit trophic effects directly on rat cardiomyocytes.