Silybin Derivatives Modulate Thyroid Hormone-Mediated UcP2 Expression in Neonatal Rat Cardiomyocytes

Thyroid hormones (TH) govern cardiac phenotype including myocardial bioenergetics, a finely tuned process, possibly by affecting expression of a number of proteins. Chronic hyperthyroidism is associated with cardiac hypertrophy, which may lead to serious heart problems perhaps through higher expression of uncoupling protein 2 (UcP2), which is present in the failing heart. We were investigating effects of silybin (SB) and dehydrosilybin (DHSB) on TH-regulated cardiomyocyte bioenergetics, including UcP2 expression levels. Both substances displayed concentration dependent down-regulation of UcP2 expression induced by THs in neonatal rat cardiomyocytes. Because DHSB uncoupled the respiration of isolated rat heart mitochondria while limiting reactive oxygen species (ROS) formation, it may be affecting UcP2 expression in a feedback control fashion. However, SB does neither. Therefore we explored the possibility of both substances limiting TH uptake into cardiomyocytes. TH presence in cardiomyocytes was evaluated by mass-spectrometry and we did not observe any limitation to the uptake of hormones. Because TH actions are primarily mediated by nuclear thyroid receptors and their transcriptional activation, we used reporter plasmid system to assess the SB and DHSB effect on thyroid hormone receptor transcriptional activity in cardiomyocytes. Our data suggest that SB and DHSB modulation of TH-mediated UcP2 expression is not related to their antioxidant ability (DHSB) or lack thereof (SB). Rather both substances influence TH-related processes by affecting the TH-dependent signaling pathway with possible beneficial effects in hyperthyroid patients.(Supported by GACR 303/08/0658 and MSM 6198959216)