Cardiac ion channel expression and contractile function in mice with deletion of thyroid hormone receptor α or β

Cardiac myocytes express the two thyroid hormone receptors (T₃Rs), T₃Rα and T₃Rβ. However, which isoform contributes to specific, T₃-induced alterations of cardiac function remains unclear. Here, we used individual T₃R isoform knockout (KO) mice to study the effects of T₃Rα and T₃Rβ in the heart. Our findings indicate that potassium channel genes that code for K⁺ channels involved in action potential repolarization, like KV 4.2 and minK, are T₃Rα targets. Both are markedly regulated by thyroid status. The recently identified cyclic nucleotide-gated channels, HCN2 and HCN4, are targets of T₃Rα and are unchanged in a euthyroid T₃Rβ KO. However, these transcripts respond markedly to altered T₃ signaling concomitant with bradycardia in T₃Rα KO and hypothyroid animals, as well as tachycardia in hyperthyroid T₃Rβ KO mice. SERCA2a and myosins are T₃ regulated and were also targets of T₃Rα, and the papillary muscles of αKO animals showed a slowed rate of force development. Because of the absence of significant cardiac effects in euthyroid T₃Rβ KO mice, we determined messenger RNA levels for both T₃Rα and T₃Rβ in the heart, We found that T₃Rβ is present at a 1:3 ratio to T₃Rα1. We conclude that the cardiac phenotype regulated by T₃ is predominantly mediated by T₃Rα and that the lack of T₃Rα cannot be compensated by T₃Rβ in the heart.