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

Cardiac myocytes express the two thyroid hormone receptors (T(3)Rs), T3R al pha and T3R beta. However, which isoform contributes to specific, T-3-induc ed alterations of cardiac function remains unclear. Here, we used individua l T3R isoform knockout (KO) mice to study the effects of T3R alpha and T3R beta 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 T3R alpha targets. Both are markedly regulated by thyroid status. The recently identified cyclic nucleotide-gated channels, HCN2 and HCN4, are targets of T3R alpha and are unchanged in a euthyroid T3R beta KO . However, these transcripts respond markedly to altered T-3 signaling conc omitant with bradycardia in T3R alpha KO and hypothyroid animals, as well a s tachycardia in hyperthyroid T3R beta KO mice. SERCA2a and myosins are T-3 regulated and were also targets of T3R alpha, and the papillary muscles of alpha KO animals showed a slowed rate of force development. Because of the absence of significant cardiac effects in euthyroid T3R beta KO mice, we d etermined messenger RNA levels for both T3R alpha and T3R beta in the heart . We found that T3R beta is present at a 1:3 ratio to T3R alpha1. We conclu de that the cardiac phenotype regulated by T-3 is predominantly mediated by T3R alpha and that the lack of T3R alpha cannot be compensated by T3R beta in the heart.