Cardiac dysfunction caused by myocardium-specific expression of a mutant thyroid hormone receptor.
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)-beta (Delta337T-TR-beta(1)) driven by the alpha-myosin heavy chain (alpha-MHC) gene promoter. As a control in these experiments, a wild-type (Wt) TR-beta(1) 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 Delta337T transgenic animals, in contrast to Wt controls or transgenic animals expressing Wt TR-beta(1), which exhibited the expected changes in steady-state MHC mRNA levels. Studies in Langendorff heart preparations from mutant TR-beta(1) 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-beta(1). 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.
Pazos-Moura
C
C
Thyroid Unit, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
Abel
E D
ED
Boers
M E
ME
Moura
E
E
Hampton
T G
TG
Wang
J
J
Morgan
J P
JP
Wondisford
F E
FE
D000818:Animals; D015870:Gene Expression; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D009154:Mutation / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics; D011988:Receptors, Thyroid Hormone / Q000235:genetics* / Q000378:metabolism*; D013379:Substrate Specificity; D019076:Transgenes / Q000502:physiology
D011988:Receptors, Thyroid Hormone; D018995:Myosin Heavy Chains