Thyroid hormone stimulates Na, K-ATPase gene expression in the hemodynamically unloaded heterotopically transplanted rat heart

Regulation of myocardial Na, K-ATPase gene expression by thyroid hormone was investigated in the heterotopically transplanted rat heart to distinguish the direct effects of the hormone on the heart from effects secondary to increased hemodynamic workload. In this model, the transplanted heart is histologically normal and spontaneously beating, but hemodynamically unloaded. Three days after transplantation, relative contents of ventricular Na, K-ATPase alpha(2)- and beta(1)-mRNAs and alpha(1)- and alpha(2)-proteins were increased twofold to threefold in the transplanted heart, but these changes were transient. We next determined the maximal triiodothyronine (T-3)-induced changes that are observed in various parameters of Na, K-ATPase expression in the heart: treatment of nontransplanted euthyroid rats with T-3 to reach hyperthyroid steady state resulted in significant increases in heart weight, RNA and RNA/protein ratio, Na, K-ATPase activity, Na, K-ATPase alpha(2)-protein and enzyme activity, and approximately threefold increase in both alpha(2)- and beta(1)-mRNA content. The effect of treatment with thyroxine (T-4) On the heterotopically transplanted and the in situ heart was then examined. T-4 treatment (of the host) resulted in a significant increase in Na, K-ATPase alpha(1)-, alpha(2)-, and beta(1)-mRNAs in transplanted hearts (1.6 +/- 0.1-, 2.4 +/- 0.2-, and 1.7 +/- 0.1-fold, respectively), that was associated with a 2.2 +/- 0.2-fold increase in alpha(2) protein as compared to transplanted hearts in diluent-treated euthyroid hosts (p < 0.05 for all changes). In addition, T-4-induced increments in transplanted hearts were similar to those observed in the corresponding in situ hearts of host rats treated with T-4. We conclude that the increase in Na, K-ATPase expression by thyroid hormone largely occurs independently of increased cardiac work elicited by the hormone and reflects a direct action of the hormone on Na, K-ATPase gene expression.