Impaired Ca2+ handling and contraction in cardiomyocytes from mice with a dominant negative thyroid hormone receptor alpha1.
The profound effects of thyroid hormone (TH) on heart development and function are mediated by the thyroid hormone receptors (TR) alpha(1) and beta(1). While numerous patients with TRbeta(1) mutations have been identified, patients with similar mutations in TRalpha(1) are yet to be discovered. Recently generated heterozygous mice with a dominant negative mutation in TRalpha(1) (TRalpha(1)+/m mice) have normal TH levels, which may have hampered the discovery of patients with such mutations. We now measure intracellular Ca(2+) and contraction in cardiomyocytes isolated from TRalpha(1)+/m mice and wildtype littermates (WT). TRalpha(1)+/m cardiomyocytes showed a phenotype similar to that in hypothyroidism with significant slowing of voltage-activated Ca(2+) transients and contractions. Increased stimulation frequency (from 0.5 to 3 Hz) or beta-adrenergic stimulation reduced the differences between TRalpha(1)+/m and WT cardiomyocytes. However, in TRalpha(1)+/m cells stimulation at 3 Hz gave a marked increase in diastolic Ca(2+) and beta-adrenergic stimulation triggered spontaneous Ca(2+) release events during relaxation. Both TRalpha(1)+/m and WT cardiomyocytes responded to TH treatment by displaying a "hyperthyroid" phenotype with faster and larger Ca(2+) transients and contractions. Excised TRalpha(1)+/m hearts showed an increased expression of phospholamban (PLB). In conclusion, isolated TRalpha(1)+/m cardiomyocytes display major dysfunctions with marked slowing of the Ca(2+) transients and contractions.
Tavi
Pasi
P
Department of Physiology and Pharmacology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
Sjögren
Maria
M
Lunde
Per Kristian
PK
Zhang
Shi-Jin
SJ
Abbate
Fabio
F
Vennström
Björn
B
Westerblad
Håkan
H
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002413:Cations, Divalent / Q000378:metabolism; D004558:Electric Stimulation; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D009154:Mutation; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation; D000099211:Phospholamban
D000318:Adrenergic beta-Agonists; D002118:Calcium; D002135:Calcium-Binding Proteins; D002413:Cations, Divalent; D007545:Isoproterenol; D037021:Thyroid Hormone Receptors alpha; D000099211:Phospholamban