Cardiac dysfunction caused by myocardium-specific expression of a mutant thyroid hormone receptor

Carmen Pazos-Moura, E. Dale Abel, Mary Ellen Boers, Egberto Moura, Thomas G. Hampton, Jufeng Wang, James P. Morgan, Fredric E. Wondisford

Research output: Contribution to journalArticlepeer-review

Abstract

Thyroid hormone deficiency has profound effects on the cardiovascular system, resulting in decreased cardiac contractility, adrenergic responsiveness, and vascular volume and increased peripheral vascular resistance. To determine the importance of direct cardiac effects in the genesis of hypothyroid cardiac dysfunction, the cardiac myocyte was specifically targeted with a mutant thyroid hormone receptor (TR)-β (Δ337T- TR-β1) driven by the α-myosin heavy chain (α-MHC) gene promoter. As a control in these experiments, a wild-type (Wt) TR-β1 was also targeted to the heart by using the same promoter. Transgenic mice expressing the mutant TR displayed an mRNA expression pattern consistent with cardiac hypothyroidism, even though their peripheral thyroid hormone levels were normal. When these animals were rendered hypothyroid or thyrotoxic, mRNA expression of MHC isoforms remained unchanged in the hearts of the Δ337T transgenic animals, in contrast to Wt controls or transgenic animals expressing Wt TR-β1, which exhibited the expected changes in steady-state MHC mRNA levels. Studies in Langendorff heart preparations from mutant TR- β1 transgenic animals revealed evidence of heart failure with a significant reduction in +dP/dT, -dP/dT, and force-frequency responses compared with values in Wt controls and transgenic mice overexpressing the Wt TR-β1. In contrast, in vivo measures of cardiac performance were similar between Wt and mutant animals, indicating that the diminished performance of the mutant transgenic heart in vitro was compensated for by other mechanisms in vivo. This is the first demonstration indicating that isolated cardiac hypothyroidism causes cardiac dysfunction in the absence of changes in the adrenergic or peripheral vascular system.

Original languageEnglish (US)
Pages (from-to)700-706
Number of pages7
JournalCirculation research
Volume86
Issue number6
DOIs
StatePublished - Mar 31 2000

Keywords

  • Cardiac hypothyroidism
  • Mice
  • Thyroid hormone resistance

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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