Details

Autor(en) / Beteiligte

• Gassanov, Natig
• Er, Fikret
• Endres-Becker, Jeannette
• Wolny, Martin
• Schramm, Christoph
• Hoppe, Uta C.

Titel

Distinct regulation of cardiac If current via thyroid receptors alpha1 and beta1

Ist Teil von

• Pflügers Archiv, 2009-10, Vol.458 (6), p.1061-1068

Ort / Verlag

Berlin/Heidelberg: Springer-Verlag

Erscheinungsjahr

2009

Quelle

Springer LINK

Beschreibungen/Notizen

• Thyroid hormone (TH) markedly modulates cardiovascular function and heart rate. The pacemaker current I f and encoding hyperpolarization-activated cation (HCN) genes have been identified as TH targets. To analyze the specific contribution and functional significance of thyroid receptor isoforms responsible for HCN gene transactivation, we generated transgenic neonatal rat cardiomyocytes with adenovirus-mediated overexpression of the thyroid receptors alpha1 (TRα1) and beta1 (TRβ1), and analyzed native I f current and expression levels of the underlying molecular components HCN2 and HCN4. Initial results revealed that spontaneous beating activity was higher in TRα1- and lower in TRβ1-expressing cardiomyocytes. This was associated with accelerated depolarization velocity and abbreviated action potential duration in cells overexpressing TRα1, while TRβ1 suppressed phase 4 depolarization and prolonged action potentials. Consistently, TRα1-infected myocytes exhibited larger I f current densities along with increased HCN2 and HCN4 mRNA and protein levels. In contrast, HCN2 gene expression was not significantly affected by TRβ1. TRβ1 exclusively suppressed HCN4 transcription. T3 application led to significant effects only in controls and TRα1-infected cardiomyocytes; whereas, no ligand-dependent actions were observed in TRβ1-expressing neonatal cardiomyocytes. Our results demonstrate that TRα1 and TRβ1 divergently regulate cardiac pacing activity. TH-induced positive chronotropic effects are likely to be mediated by TRα1 through enhanced expression of I f pacemaker current and its underlying genes.