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Cardiac ion channel expression and contractile function in mice with deletion of thyroid hormone receptor alpha or
1Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California 92093, USA.
Abstract:
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.
Insights
Thyroid hormone receptor alpha (T(3)Ralpha) predominantly controls cardiac function by regulating key ion channels and proteins. The T(3)Rbeta isoform does not compensate for T(3)Ralpha
Area of Science:
- Cardiovascular Physiology
- Endocrinology
- Molecular Biology
Background:
- Cardiac myocytes express both thyroid hormone receptors (T(3)Ralpha and T(3)Rbeta).
- The specific roles of each T(3)R isoform in mediating thyroid hormone-induced cardiac alterations are not fully understood.
Purpose of the Study:
- To elucidate the distinct contributions of T(3)Ralpha and T(3)Rbeta to thyroid hormone regulation of cardiac function using isoform-specific knockout mice.
Main Methods:
- Utilized individual T(3)R isoform knockout (KO) mouse models.
- Analyzed the expression of potassium channel genes (KV 4.2, minK, HCN2, HCN4), SERCA2a, and myosins.
- Assessed cardiac muscle contractility (papillary muscles) and heart rate responses.
Main Results:
- T(3)Ralpha directly targets potassium channel genes (KV 4.2, minK, HCN2, HCN4) and genes involved in contractility (SERCA2a, myosins).
- T(3)Ralpha deficiency led to altered action potential repolarization and slowed force development in papillary muscles.
- T(3)Rbeta knockout mice showed no significant cardiac effects in the euthyroid state, despite T(3)Rbeta's presence in cardiac tissue.
Conclusions:
- Cardiac function regulation by thyroid hormone is primarily mediated by the T(3)Ralpha isoform.
- T(3)Rbeta cannot compensate for the loss of T(3)Ralpha in the heart.
- These findings highlight T(3)Ralpha as the key mediator of thyroid hormone effects on cardiac electrophysiology and contractility.