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), T(3)Ralpha and T(3)Rbeta. However, which isoform contributes to specific, T(3)-induced alterations of cardiac function remains unclear. Here, we used individual T(3)R isoform knockout (KO) mice to study the effects of T(3)Ralpha and T(3)Rbeta 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 T(3)Ralpha targets. Both are markedly regulated by thyroid status. The recently identified cyclic nucleotide-gated channels, HCN2 and HCN4, are targets of T(3)Ralpha and are unchanged in a euthyroid T(3)Rbeta KO. However, these transcripts respond markedly to altered T(3) signaling concomitant with bradycardia in T(3)Ralpha KO and hypothyroid animals, as well as tachycardia in hyperthyroid T(3)Rss KO mice. SERCA2a and myosins are T(3) regulated and were also targets of T(3)Ralpha, and the papillary muscles of alphaKO animals showed a slowed rate of force development. Because of the absence of significant cardiac effects in euthyroid T(3)Rss KO mice, we determined messenger RNA levels for both T(3)Ralpha and T(3)Rss in the heart. We found that T(3)Rss is present at a 1:3 ratio to T(3)Ralpha1. We conclude that the cardiac phenotype regulated by T(3) is predominantly mediated by T(3)Ralpha and that the lack of T(3)Ralpha cannot be compensated by T(3)Rss in the heart.
Gloss
B
B
Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California 92093, USA.
Trost
S
S
Bluhm
W
W
Swanson
E
E
Clark
R
R
Winkfein
R
R
Janzen
K
K
Giles
W
W
Chassande
O
O
Samarut
J
J
Dillmann
W
W
D000818:Animals; D003285:Contractile Proteins / Q000235:genetics; D054815:Cyclic Nucleotide-Gated Cation Channels; D006325:Heart Atria; D006339:Heart Rate; D006352:Heart Ventricles; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D066298:In Vitro Techniques; D007473:Ion Channels / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009124:Muscle Proteins; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000172:deficiency* / Q000235:genetics
D003285:Contractile Proteins; D054815:Cyclic Nucleotide-Gated Cation Channels; C578710:HCN2 protein, human; C119587:HCN4 protein, human; C578711:Hcn2 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D009124:Muscle Proteins; D015221:Potassium Channels; D020033:Protein Isoforms; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone