Absence of Myocardial Thyroid Hormone Inactivating Deiodinase Results in Restrictive Cardiomyopathy in Mice

Abstract

Cardiac injury induces myocardial expression of the thyroid hormone inactivating type 3 deiodinase (D3), which in turn dampens local thyroid hormone signaling. Here, we show that the D3 gene (Dio3) is a tissue-specific imprinted gene in the heart, and thus, heterozygous D3 knockout (HtzD3KO) mice constitute a model of cardiac D3 inactivation in an otherwise systemically euthyroid animal. HtzD3KO newborns have normal hearts but later develop restrictive cardiomyopathy due to cardiac-specific increase in thyroid hormone signaling, including myocardial fibrosis, impaired myocardial contractility, and diastolic dysfunction. In wild-type littermates, treatment with isoproterenol-induced myocardial D3 activity and an increase in the left ventricular volumes, typical of cardiac remodeling and dilatation. Remarkably, isoproterenol-treated HtzD3KO mice experienced a further decrease in left ventricular volumes with worsening of the diastolic dysfunction and the restrictive cardiomyopathy, resulting in congestive heart failure and increased mortality. These findings reveal crucial roles for Dio3 in heart function and remodeling, which may have pathophysiologic implications for human restrictive cardiomyopathy.

Genomic imprinting of DIO3, a candidate gene for the syndrome associated with human uniparental disomy of chromosome 14

“…Observations in a mouse model of genetic inactivation of the paternal Dio3 allele, a model comparable to Temple syndrome in humans, indicate elevated levels of thyroid hormone at neonatal stages, 21 but not in adulthood. 24 However, owing to timing differences in brain developmental processes, the hypothalamic-pituitary-thyroid axis is already mature in human newborns, whereas it is still immature in newborn rodents. It is thus possible that abnormal thyroid hormone exposure occurs in utero in patients with the above syndromes.…”

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…8). For example, ischemia and hypoxia cause the brain and the heart to become acutely hypothyroid in an otherwise euthyroid animal due to induction of type III deiodinase (D3) expression (62)(63)(64)(65). At the same time, the brown adipose tissue (BAT) exhibits localized increase in thyroid hormone signaling shortly after rodents are moved to the cold due to acute induction of type II deiodinase (D2) expression (66).…”

“…This is also observed in animal models of transgenic Dio2 expression in the heart (273,274). In contrast, D3 inactivation results in localized increase in thyroid hormone signaling as evidenced in the D3 KO mouse (64,239,(275)(276)(277)(278)(279).…”

“…These methodologies are also used to assess the role of cardiac thyroid-hormone signaling in genetically modified mice, such as TR knock-out models (451), and in models of pathological cardiac remodeling and heart failure. Models for LV remodeling include the spontaneously hypertensive rat model (539); surgical induction of myocardial infarction by transient or permanent ligation of the left descending coronary artery (238,540); LV pressure overload by surgical banding of the aorta (transverse aortic constriction) (541)(542)(543)(544); and isoproterenol-induced LV hypertrophy in the context of the D3 knock-out mouse model (64). Involvement of thyroid-hormone signaling in right-ventricular (RV) remodeling has been studied in rat using the model of pulmonary arterial hypertension induced by a single injection of monocrotaline (62,63).…”

“…reactivation during illness, ischemia, or hypoxia that leads to localized disruption in thyroid hormone signaling in different tissues such as myocardium and brain (62)(63)(64)(65)238,241).…”