title: Impaired Ca2+ handling and contraction in cardiomyocytes from mice with a dominant negative thyroid hormone receptor alpha1.
abstract: 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.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
authors.forename: Pasi
authors.initials: P
authors.lastname: Tavi
authors.forename: Maria
authors.initials: M
authors.lastname: Sjögren
authors.forename: Per Kristian
authors.initials: PK
authors.lastname: Lunde
authors.forename: Shi-Jin
authors.initials: SJ
authors.lastname: Zhang
authors.forename: Fabio
authors.initials: F
authors.lastname: Abbate
authors.forename: Björn
authors.initials: B
authors.lastname: Vennström
authors.forename: Håkan
authors.initials: H
authors.lastname: Westerblad
mesh_terms: 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
chemical_list: D000318:Adrenergic beta-Agonists; D002118:Calcium; D002135:Calcium-Binding Proteins; D002413:Cations, Divalent; D007545:Isoproterenol; D037021:Thyroid Hormone Receptors alpha; D000099211:Phospholamban