Thyroid hormone receptor α1: A switch to cardiac cell "metamorphosis"?

Thyroid hormone receptor α1 (TRα1) is predominantly expressed in the myocardium but its biological function under physiological or pathological conditions remains largely unknown. The present study investigated possible interactions between α1 adrenergic and thyroid hormone signaling at the level of TRα1, potential underlying mechanisms and physiological consequences, as well as the role of TRα1 in cell differentiation. This may be of physiological relevance since both thyroid hormone and adrenergic signalling are implicated in the pathophysiology of cardiac remodelling. Neonatal cardiomyocytes obtained from newborn rats (2-3 days) were exposed to phenylephrine (PE, an α1 adrenergic agonist) for 5 days, in the absence or excess of T3 in the culture medium. PE, in the absence of T3, resulted in 5.0 fold increase in TRα1 expression in nucleus and 2.0 fold decrease in TRα1 expression in cytosol, P<0.05. As a result, a fetal pattern of myosin isoform expression with marked expression of β-MHC was observed in PE treated vs the untreated cells, P<0.05. PD98059 (an ERK signalling inhibitor) abrogated this response. In the presence of T3 in the culture medium, TRα1 expression was increased 1.6 fold in nucleus and 2.0 fold in cytosol in PE-T3 vs PE treated cells, P<0.05, and the fetal pattern of myosin isoform expression was prevented. Parallel studies with H9c2 myoblasts showed that reduction of T3 binding to TRα1 receptor delayed cardiac myoblasts differentiation without affecting proliferation. In conclusion, in neonatal cardiomyocytes, nuclear TRα1 is overexpressed after prolonged activation of the α1- adrenergic signalling by PE. This response seems to be an ERK kinase dependent process. Over-expression of TRα1 may lead to fetal cardiac phenotype in the absence of thyroid hormone availability. Furthermore, TRα1 seems to be critical in cardiac myoblast differentiation.