Cardiac Dysfunction Caused by Myocardium-Specific Expression of a Mutant Thyroid Hormone Receptor

Pazos‐Moura, Carmen C.; Abel, E. Dale; Boers, Mary Ellen; Moura, Egberto Gaspar de; Hampton, Thomas G.; Wang, Jufeng; Morgan, James P.; Wondisford, Fredric E.

doi:10.1161/01.res.86.6.700

Cited by 38 publications

(38 citation statements)

References 28 publications

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“…These data also confirmed that the adult mutant mice devoid of TR␣ are bradycardic (14,15,(22)(23)(24). They further show that the basal HR of both WT and mutant pregnant mice is slightly elevated as compared with nonpregnant animals with the respective genotype.…”

Section: Discussionsupporting

confidence: 77%

Thyroid hormone receptor α is a molecular switch of cardiac function between fetal and postnatal life

Maï

Janier

Allioli

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

112

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Thyroid hormones are involved in the regulation of many physiological processes and regulate gene transcription by binding to their nuclear receptors TR␣ and TR␤. In the absence of triiodothyronine (T3), the unliganded receptors (aporeceptors) do bind DNA and repress the transcription of target genes. The role of thyroid hormone aporeceptors as repressors was observed in hypothyroid adult mice, but its physiological relevance in nonpathological hypothyroid conditions remained to be determined. Here we show that, in the normal mouse fetus, TR␣ aporeceptors repress heart rate as well as the expression of TR␤ and several genes encoding ion channels involved in cardiac contractile activity. Right after birth, when T3 concentration sharply increases, liganded TR␣ (holoreceptors) turn on the expression of some of these same genes concomitantly with heart rate increase. These data describe a physiological situation under which conversion of TR␣ from apo-receptors into holo-receptors, upon changes in T3 availability, plays a determinant role in a developmental process.

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Section: Discussionsupporting

confidence: 77%

Thyroid hormone receptor α is a molecular switch of cardiac function between fetal and postnatal life

Maï

Janier

Allioli

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

112

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“…1A). The artificially reduced levels of elastance and contractile function, and enhanced diastolic stiffness measured with these smaller balloons are consistent with values measured previously (Brooks & Apstein, 1996;Kameyama et al 1998;Pazos-Moura et al 2000;Sam et al 2000). Thus, low contractility in some prior studies may reflect the effects of inadequate balloon design.…”

Section: Normoxic Function and Stabilitysupporting

confidence: 87%

“…Estimates of left ventricular developed pressure and +dP/dt for isolated mouse hearts vary from as low as 5MO mmHg and 1000-3000 nlmHg s-', respectively Kameyama et al 1998;Sat0 et al 1998;Gyurko et al 2000;Pazos-Moura et al 2000;Zhao et al 2000;MacGowan et al 2001), to greater than 110 mmHg and 4000-6000 mmHg s-', respectively (Brooks & Apstein, 1996;Headrick et al 2000a;Sam et al 2000). These values compare with in situ left ventricular pressures of -1 10 mmHg (Georgakopoulos et al 1998), and +dPldt values L 8000 mmHg s-' (Hoit et al 1997;Georgakopoulos et al 1998).…”

Section: Normoxic Function and Stabilitymentioning

confidence: 99%

“…1998;Bartfay et al 1999;Flogel et al 1999;. Even in recent studies in isolated murine hearts, levels of ventricular contractility hme been reported to be below 25-30% of in situ values (Pazos-Moura et al 2000;Tardiff et al 2000;Zhao et al 2000;MacGowan et al 2001). Greater efforts are esseiitial to define the normal range of cardiac function in different murine models , and to develop improved models with which to study cardiovascular physiology, pharmacology and biochemistry.…”

mentioning

confidence: 99%

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Functional properties and responses to ischaemia‐reperfusion in Langendorff perfused mouse heart

Headrick¹,

Peart²,

Hack³

et al. 2001

Experimental Physiology

112

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Despite minimal model characterisation Langendorff perfused murine hearts are increasingly employed in cardiovascular research, and particularly in studies of myocardial ischaemia and reperfusion. Reported contractility remains poor and ischaemic recoveries variable. We characterised function in C57/BL6 mouse hearts using a ventricular balloon or apicobasal displacement and assessed responses to 10-30 min global ischaemia. We examined the functional effects of pacing, ventricular balloon design, perfusate filtration, [Ca"] and temperature. Contractility was high in isovolumically functioning mouse hearts (measured as the change in pressure with time (+dP/dt), 6000-7000 mmHg s-I) and was optimal at a heart rate of -420 beats min-', with the vasculature sub-maximally dilated, and the cellular energy state high. Post-ischaemic recovery (after 40 min reperfusion) was related to the ischaemic duration: developed pressure recovered by 82 f YO, 73 f 4u/, 68 f 3%, 57 f 2% and 41 f 5% after 10, 15, 20, 25 and 30 min ischaemia, respectively. Ventricular compliance and elastance were both reduced post-ischaemia. Post-ischaemic recoveries were lower in the apicobasal model (80 +-4 YO, 58 k 7 YO, 40 +-3 %, 32 +-7 % and 25 2 5 YO) despite greater reflow and lower metabolic rate (pre-ischaemic myocardial O2 consumption (Vo2,,,,) 127 f 15 vs. 198 k 17 p l O2 min-' g-'), contracture, enzyme and purine efflux. Electrical pacing slowed recovery in both models, small ventricular balloons (unpressurised volumes C 50-60 p1) artificially depressed ventricular function and recovery from ischaemia, and failure to filter the perfusion fluid to C 0.45 pm depressed pre-and post-ischaemic function. With attention to these various experimental factors, the buffer perfused isovolumically contracting mouse heart is shown to be stable and highly energised, and to possess a high level of contractility, The isovolumic model is more reliable in assessing ischaemic responses than the commonly employed apicobasal model. Experimental Physiology (200 1) 86.6, 703-7 16.

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“…Here, we used mice that express the TRbD337T, which cannot bind TH, being constitutively associated with CoR and acting as a potent dominant negative inhibitor of the WT TR (Safer et al 1998, Pazos-Moura et al 2000, Hashimoto et al 2001). This mouse model reproduces the human syndrome of resistance to TH (Hashimoto et al 2001).…”

Section: Introductionmentioning

confidence: 99%

The Δ337T mutation on the TRβ causes alterations in growth, adiposity, and hepatic glucose homeostasis in mice

Santiago¹,

Santiago²,

Faustino³

et al. 2011

Journal of Endocrinology

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Mice bearing the genomic mutation D337T on the thyroid hormone receptor b (TRb) gene present the classical signs of resistance to thyroid hormone (TH), with high serum TH and TSH. This mutant TR is unable to bind TH, remains constitutively bound to co-repressors, and has a dominant negative effect on normal TRs. In this study, we show that homozygous (TRbD337T) mice for this mutation have reduced body weight, length, and body fat content, despite augmented relative food intake and relative increase in serum leptin. TRbD337T mice exhibited normal glycemia and were more tolerant to an i.p. glucose load accompanied by reduced insulin secretion. Higher insulin sensitivity was observed after single insulin injection, when the TRbD337T mice developed a profound hypoglycemia. Impaired hepatic glucose production was confirmed by the reduction in glucose generation after pyruvate administration.In addition, hepatic glycogen content was lower in homozygous TRbD337T mice than in wild type. Collectively, the data suggest that TRbD337T mice have deficient hepatic glucose production, by reduced gluconeogenesis and lower glycogen deposits. Analysis of liver gluconeogenic gene expression showed a reduction in the mRNA of phosphoenolpyruvate carboxykinase, a rate-limiting enzyme, and of peroxisome proliferator-activated receptor-g coactivator 1a, a key transcriptional factor essential to gluconeogenesis. Reduction in both gene expressions is consistent with resistance to TH action via TRb, reproducing a hypothyroid phenotype. In conclusion, mice carrying the D337T-dominant negative mutation on the TRb are leaner, exhibit impaired hepatic glucose production, and are more sensitive to hypoglycemic effects of insulin.

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Cardiac Dysfunction Caused by Myocardium-Specific Expression of a Mutant Thyroid Hormone Receptor

Cited by 38 publications

References 28 publications

Thyroid hormone receptor α is a molecular switch of cardiac function between fetal and postnatal life

Thyroid hormone receptor α is a molecular switch of cardiac function between fetal and postnatal life

Functional properties and responses to ischaemia‐reperfusion in Langendorff perfused mouse heart

The Δ337T mutation on the TRβ causes alterations in growth, adiposity, and hepatic glucose homeostasis in mice

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