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Thyroid Disorders
Table 1: Genes Involved in the Regulation of Heart
heart rate. Compared with wt mice, TRβ
-/-
showed similar decreases and
Activities, Presenting T
3
Response Elements
increases in HR in response to TH deprivation and L-T
3
treatment,
respectively.
24
Deletion of both TRα1 and TRβ results in a similar phenotype
Positively Regulated Negatively Regulated to TRα1
-/-
mice, suggesting a crucial role of TRα1 in specific heart
Myosin heavy chain-α
functions, namely regulation of pacemaker function and ventricular
L-type calcium channel
repolarization.
22,23
Transgenic KO of both TRα1 and TRα2 causes bradycardia
Ryanodine calcium channel Myosin heavy chain-β
and decreased myocardial contractility.
25
In these particular transgenic
Voltage-gated potassium channels Phospholamban
mice, HR increases with the administration of L-T
Na
+
/K
+
-ATPase Adenylyl cyclase catalytic subunits
3
. This observation
β-1-adrenergic receptor Thyroid hormone receptor alpha 1
suggests that in the absence of TRα the heart rate is in the hypothyroid
Atrial natriuretic hormone Na
+
/Ca
2+
exchanger
range, but can still be increased by TH, probably acting through the TRβ.
25
Voltage-gated potassium channel
A reduction of HCN2 and HCN4 expression (genes coding for the cardiac
Sarcoplasmic reticulum Ca2
+
-ATPase
pacemaker current)
26,27
has been described. Moreover, these mice exhibit a
11 reduced cardiac sensitivity to dynamic testing, supporting the hypothesis
ATP = adenosine triphosphate. Modified from Klein and Danzi.
that TRα is the major functional cardiac TR isoform.
21,25
The increased levels
Figure 1: Possible Mechanisms Involved in Dominant
of HCN2 and HCN4 in TRβ
-/-
mice may be linked to TRα-mediated T
3
Negative Effect—Mutant Thyroid Hormone Receptor
Interferes with the Function of Normal Thyroid
responsiveness, in fact reducing the high levels of TH in TRβ
-/-
; heart rate
Hormone Receptor
and HCN gene expression tend to normalize.
27
Mice ‘knock-in’ models
28–35
have been generated in order to better
TR
CoAct
TR
RXR TR TR
Mut CoR understand the cardiac phenotype of RTH subjects. The PV mutation
Mut
Mut WT TR
consists of a C-insertion at codon 448 in exon 10, which produces aMut
TR
RXR
TR
TRWT
frameshift of the carboxyl-terminal 14 amino acids of TRβ1 resulting in
TR
Mut
Mut
RXR
WT
a complete loss of TH-binding activity.
31
The TRα
PV/+
and TRβ
PV/PV
TRE TRE
mutations lead, respectively, to opposite effects on energy metabolism in
Competition Capture the heart:
28
cardiac glucose utilization was reduced in the TRα
PV/+
mutants
and markedly enhanced in TRβ
PV/PV
. Moreover, TRα
PV/+
show a reduction
TR in heart size and blood pressure compared with wt mice, while heart sizeTR
T3 T3RXR
RXR
WT Mut
and blood pressure were normal in TRβ
PV/PV
mice. These data appear toCoAct
TRE TRE
be consistent with the alterations in cardiac function, such as bradycardia
and reduced cardiac output, found in hypothyroidism and tachycardiaCoR
TRTR TR TR TR
T3 RXR
T3
Mut T3Mut Mut Mut WT
associated with hyperthyroidism and RTH.
TRETRE TRE
Svanson and collaborators
32
reported a decreased heart rate and a
Inhibition Silencing
diminished contractile function in TRβ
PV/PV
mice when thyroid hormone
RXR = retinoid X receptor; TR = thyroid hormone receptor; WT = wild type; MUT = mutant;
TRE = thyroid hormone response element; CoR = co-repressor; CoAct = co-activator. levels were lowered into the normal range, suggesting that the
homozygous PV mutant can negatively interfere with TRα1 signaling in
GRTH and PRTH patients and even patients belonging to the same family the heart. These effects on the heart rate may be explained in part by a
may present with either form. As an example, both GRTH and PRTH decreased expression of the ion channels. By contrast, the absence of
patients have resistance in the liver as documented by the measurement functional consequences in TRβ
PV/PV
mutant mice with elevated thyroid
of sex-hormone-binding globulin, a peripheral marker of thyroid hormone hormone levels is likely due to an increased occupancy of TRα1. The
action, whose levels are in the normal range, thus failing to distinguish expression of a mutant TRβ (Δ337T) in heart mice, driven by a
between the two forms.
17,18
The variability of the phenotype of subjects β-actin promoter
33
or an MHCα promoter,
34
induces a hypothyroid
with RTH, including cardiac manifestations, derives from the different phenotype in the heart, despite normal T
3
, thyroxine (T
4
), and TSH levels
expression of TR isoforms in target tissue, which determines the different in these mice. In isolated hearts particularly, the impairment of thyroid
responsiveness to TH.
12
TRβ is expressed mainly in the hypothalamus, hormone action leads to left ventricular dysfunction; indeed, the cardiac
kidney, liver, anterior pituitary gland, hypothalamus, retina, and cochlea, performance measured in vivo is similar between wt and mutant
whereas TRα predominates in the skeletal and cardiac muscle, brain, animals, suggesting that other mechanisms could compensate in vivo
heart, brown fat, intestine, spleen, and vascular endothelial cells. the abnormalities of the mutant transgenic heart.
34
These findings are
consistent with a dominant negative interference of wt TR function by the
Animal Model of Resistance to Thyroid Hormone mutant TR and provide insight into the observation of the relative
Data from knock-out (KO) mice suggest that TH achieve their action on the impairment in cardiac contractility seen in many patients with RTH.
39,40
heart predominantly via TRα1.
4,19–38
In TRα1
-/-
mice, reduced heart rate (HR) Indeed, the effects of RTH on the heart are complex and not completely
and prolonged QRS- and QT-end-durations have been described. After T
3
explained by the heightened T
3
/TRα1 signaling, as suggested by the
administration, HR increases in TRα1
-/-
mice, but to a much lesser degree discordant cardiac gene expression profile between WT mice treated
compared with wt mice, even after prolonged exposure to high doses.
22
with T
3
and TRβ
PV/PV
.
35
Recently, it has been suggested that while TRα
Conversely, TRβ
-/-
mice display a reduced QT end time
23
and an increased may be crucial for contractility, the β isoform could be involved in the
118 US ENDOCRINOLOGY
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