© 2001 American Heart Association, Inc.
Cellular Biology |
Thyroid Hormone Activation in Human Vascular Smooth Muscle Cells
Expression of Type II Iodothyronine Deiodinase
From the First Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Japan.
Correspondence to Masami Murakami, MD, First Department of Internal Medicine, Gunma University School of Medicine, Maebashi 371-8511, Japan. E-mail mmurakam{at}showa.gunma-u.ac.jp
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Abstract |
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Abstract—Thyroid hormone has been reported to have significant effects on the peripheral vascular system, including relaxation of vascular smooth muscle cells and antiatherosclerotic effects. To exert its biological activity, thyroxine, which is a major secretory product of thyroid gland, needs to be converted to 3,5,3'-triiodothyronine (T3) by iodothyronine deiodinase. Type I iodothyronine deiodinase (DI) is widely distributed and maintains circulating T3 level, whereas type II iodothyronine deiodinase (DII) is present in a limited number of tissues to provide local intracellular T3. In the present study, we have identified iodothyronine deiodinase in cultured human coronary artery smooth muscle cells (hCASMCs) and human aortic smooth muscle cells (hASMCs). All of the characteristics of the deiodinating activity in hCASMCs and hASMCs were compatible with DII. Northern analysis demonstrated that DII mRNA was expressed in both hCASMCs and hASMCs, and DII mRNA levels as well as DII activities were rapidly increased by dibutyryl-cAMP or forskolin. These data demonstrate, for the first time, the expression of DII in human vascular smooth muscle cells, which is regulated by a cAMP-mediated mechanism. The present results suggest a previously unrecognized role of local T3 production by DII in the pathophysiology of human vascular smooth muscle cells.
Key Words: coronary artery smooth muscle • aortic smooth muscle • thyroid hormone receptor • cAMP
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Introduction |
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Thyroid hormone has profound effects on the peripheral vascular system. It is known as a vasodilator that acts directly on vascular smooth muscle cells (SMCs) to cause a relaxation of coronary arteries.1 2 Hypothyroidism is known to be a risk factor for atherosclerosis, and thyroid hormone replacement in hypothyroidism has been reported to protect from atherosclerosis.3 4
To exert its biological activity, thyroxine
(T4), which is a major secretory product of the
thyroid gland, needs to be converted to 3,5,3'-triiodothyronine
(T3) by iodothyronine
deiodinase.5 6
There are two types, type I iodothyronine deiodinase (DI) and type II
iodothyronine deiodinase (DII), which catalyze conversion of
T4 to T3. DI is present
in thyroid gland, liver, kidney, and many other tissues, whereas DII is
present in a limited number of tissues, including central nervous
system, anterior pituitary tissue, and brown fat in the
rat.5 6
Km of
DII is 
2 nmol/L for T4, which is a hundred
times lower than that of DI. DI activity is known to decrease in the
hypothyroid state and is believed to have a primary role in maintaining
circulating T3 levels. DII activity, in
contrast, increases in the hypothyroid state and is considered to play
a critical role in providing local T3 to
regulate intracellular T3
concentration.5 6
Although the source of T3 mainly depends on
circulating T3 in most tissues, local
intracellular conversion of T4 to
T3 is an important source of
T3 in certain tissues where DII
exists.5 6
A cDNA encoding DII was cloned from Rana catesbeiana tissues,7 and its mammalian counterpart was subsequently isolated from rat brown fat.8 In human, DII mRNA was unexpectedly detected in thyroid gland and other tissues, suggesting previously unrecognized roles of DII in those tissues.9 10 Considering that not only T3, but also T4 has been reported to have effects on peripheral vascular function,11 12 13 DII may exist in vascular SMCs and may contribute to the pathophysiology of human vascular systems by providing intracellular T3.
In the present study, we have characterized iodothyronine deiodinating activity and identified DII expression in cultured human coronary artery SMCs (hCASMCs) and human aortic SMCs (hASMCs).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Materials
[
32P]UTP,
125I-labeled 3,3',5'-triiodothyronine
(reverse T3
[rT3]), and
[125I]T4 were
purchased from New England Nuclear Corp. AG 50W-X2 resin and protein
assay kit were from Bio-Rad Laboratories, Inc. All other chemicals were
obtained from Sigma Chemical Company or Wako Pure Chemical Industries,
Ltd, unless otherwise indicated.
Cell Culture
hCASMCs were obtained from Clonetics, and hASMCs were
from Cascade Biologics. Both cells were demonstrated to express
-smooth muscle actin isoform but not factor VIII, indicating the
nature of vascular SMCs. These cells were inoculated to 6-well plastic
culture plates for the measurement of deiodinase activity or to 60-mm
plastic culture dishes for Northern analysis, and the cells were
cultured in modified MCDB 131 medium (HuMedia-SG2, KURABO,
Osaka, Japan) as previously
described.14 After the cells
became confluent, the medium was displaced with serum-free medium to
arrest the proliferation of cells for 48 hours. The cells were then
incubated in the medium containing compounds to be tested for indicated
hours.
Measurement of Deiodinase Activity
Iodothyronine deiodinase activity was measured as
previously described15 with
minor modifications.16
Briefly, SMCs per each well (2.0x106
cells per well) were washed twice with the washing buffer (100 mmol/L
potassium phosphate, pH 7.0), scraped off, and transferred into 1000
µL of ice-cold buffer (100 mmol/L potassium phosphate, pH 7.0,
containing 20 mmol/L DTT). After centrifugation at 3000 rpm for 15
minutes at 4°C, the supernatant was discarded. Pellets were sonicated
in 100 µL of the assay buffer (in mmol/L, potassium phosphate [pH
7.0] 100, containing EDTA 1 and DTT 20) per tube and were incubated
with indicated amounts of
[125I]rT3 or
[125I]T4, which was
purified on the day of experiment, in the presence or absence of 1
mmol/L 6-propyl-2-thiouracil (PTU) or 1 mmol/L iopanoic acid.
The reaction was terminated by adding 100 µL of 2% BSA and 800 µL
of 10% trichloroacetic acid. The released
125I was separated by column chromatography
using AG 50W-X2 resin as previously
described16 and counted. The
protein concentration was determined by the Bradford method using BSA
as a standard.17 The
deiodinating activity was calculated either as percentage
I- released or as femtomoles of
I- released/mg protein per hour. After the
characterization of deiodinase activity, the deiodinating activity was
measured in duplicate by I- release from 2
nmol/L [125I]T4 in
the presence of 1 mmol/L PTU at 37°C for 1
hour.
Northern Analysis and Reverse
Transcription–Polymerase Chain Reaction (RT-PCR)
Northern analysis and RT-PCR were performed as
previously
described.14 18 19
Total RNA was isolated from each dish, thyroid tissue, which was
obtained from a patient with Graves’ disease, and cerebral cortical
tissue, which was obtained from an autopsy case. In Northern analysis,
mRNA levels were quantified by densitometry, and the optical density of
the DII band was corrected for GAPDH. RNA samples for comparison were
analyzed on the same blot, and each experiment was performed at least
twice with basically identical results.
Statistics
All values are expressed as mean±SE. Statistical
differences were evaluated by Student
t
test.
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Results |
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Characteristics of Iodothyronine Deiodinase in hCASMCs and hASMCs
The deiodinating activity in hCASMCs was measured by the release of I- from 2 nmol/L [125I]T4 or [125I]rT3 in the presence of 20 mmol/L DTT and 1 mmol/L PTU. T4 deiodination was dependent on an incubation period up to 2 hours, as shown in Figure 1A
and protein concentration of hCASMCs, as shown in
Figure 1B. Optimal pH for the deiodination was 7.0.
Incubation at 4°C or preheating the cell sonicate at 56°C for 30
minutes completely abolished the deiodination. Both the
T4 and rT3 deiodinating
activities were not influenced by 1 mmol/L PTU, but were completely
inhibited by 1 mmol/L iopanoic acid. Basically identical results were
obtained for hASMCs. From the double reciprocal plot, kinetic constants
for T4 were calculated to be
Km=2.3
nmol/L and Vmax=333.3 fmol
I- released/mg protein per hour in
hCASMCs, as shown in
Figure 1C. Vmax for
rT3 in hCASMCs was lower than that for
T4
(Table).
In hASMCs, kinetic constants for T4 and
rT3 were comparable with those in hCASMCs
(Table).
When we fractionated the hCASMC
preparation,9 the highest
deiodinating activity was observed in microsomal fraction (755.4 versus
295.3 [total cell homogenate] fmol I-
released/mg protein per hour). Taken together, these results indicate
that the characteristics of the deiodinating activity in hCASMCs and
hASMCs are compatible with DII.
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Identification of DII mRNA in Cultured hCASMCs
and hASMCs
Northern analysis using human DII cRNA probe was
performed to examine whether DII mRNA is expressed in human vascular
SMCs. As shown in
Figure 2, hybridization signals of DII mRNA 7.5 kb in
size were clearly demonstrated in hCASMCs and hASMCs. The size of DII
mRNA in hCASMCs and hASMCs was indistinguishable from that in human
thyroid gland,9 although the
amount of DII mRNA in hCASMCs or hASMCs was less than that in human
thyroid gland. These results indicate that DII mRNA is expressed in
both hCASMCs and hASMCs.
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Regulation of DII Expression in Cultured
hCASMCs and hASMCs by Thyroid Hormones
One of the important characteristics of DII is the
negative regulation of its activity by thyroid
hormones.5 6 To
study the effects of thyroid hormones on deiodinating activity in human
vascular SMCs, thyroid hormones were added to the culture medium for 6
hours before the harvest of cultured SMCs. As shown in
Figure 3A, the deiodinating activity was decreased by
thyroid hormones, and the potency of the inhibitory effect was
T4>rT3>T3
in hCASMCs. Although the deiodinating activity was measured by the
release of I- from
[125I]T4, control
studies demonstrated that the effects of T4 or
rT3 on the deiodinating activity were time
dependent and are thus not explained by dilution of the substrate with
T4 or rT3 carried over
into the assay of deiodinase activity. More importantly,
10-7 mol/L
rT3 added to the assay buffer of deiodinase
activity did not affect the release of I-
from [125I]T4. DII
mRNA in hCASMCs was inhibited by thyroid hormones; the potency of the
inhibitory effect was
T3>T4>rT3,
as shown in
Figure 3B. Basically identical inhibitory effects of thyroid
hormones on the deiodinating activity and DII mRNA expression were
observed in hASMCs. Inhibition of the deiodinating activity in hCASMCs
and hASMCs by thyroid hormones further indicates the presence of
authentic DII activity in cultured hCASMCs and hASMCs. These results
suggest that T3 suppresses DII activity mainly
at the pretranslational level, whereas T4 or
rT3 suppresses DII activity largely at the
post-translational level in hCASMCs and hASMCs, in agreement with
previous observations for DII in other tissues and
cells.14 20 21 22
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Stimulation of DII Expression in Cultured
hCASMCs and hASMCs by Forskolin or Dibutyryl cAMP
([Bu]2cAMP)
Because DII activity has been known to be regulated by
a cAMP-dependent
mechanism,5 6 the
effects of cAMP-elevating agents on DII expression in human vascular
SMCs were studied. As shown in
Figures 4A and 4B, DII activity and DII mRNA in cultured
hCASMCs were clearly increased by treatment with forskolin
(10-5 mol/L) or
(Bu)2cAMP
(10-3 mol/L)
for 6 hours. In the time-course study, both DII activity and DII mRNA
in cultured hCASMCs were increased by forskolin within 3 hours, as
shown in
Figure 5. When actinomycin D (5 µg/mL) was added to the
culture medium 30 minutes before the incubation with forskolin
(10-5 mol/L)
for 6 hours, the stimulation of DII activity was completely abolished,
indicating the requirement of mRNA synthesis for the stimulation of DII
activity by a cAMP-mediated mechanism. Forskolin stimulated DII
activity and DII mRNA in hASMCs in the same manner, as shown in
Figure 6.
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, DII mRNA (DII mRNA/GAPDH mRNA ratio) in hCASMCs incubated with forskolin for various hours. Optical density of the DII band was corrected for GAPDH, and results are expressed as a percentage of the value obtained for control (0 hours).
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Identification of Thyroid Hormone Receptor (TR)
Isoforms in Cultured hCASMCs and hASMCs by RT-PCR
To investigate whether TRs are expressed in hCASMCs and
hASMCs, we have performed RT-PCR analyses of TR isoforms in those
cells. In control human cerebral cortical tissue, all of the TR
isoforms were clearly demonstrated by RT-PCR, as shown in
Figure 7. Although all of the TR isoforms were also
detected in both hCASMCs and hASMCs by RT-PCR, strong expression of
mRNA for TR1 and TR2 isoforms and relatively weak expression of
mRNA for TRß1 and TRß2 were observed in both hCASMCs and hASMCs, as
shown in
Figure 7.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present results have clearly demonstrated that iodothyronine deiodinating activities are present in cultured hCASMCs and hASMCs. The deiodinating activities in hCASMCs and hASMCs were dependent on the protein concentrations, incubation period, pH, temperature, and substrate concentrations. These characteristics clearly indicate the enzymatic nature of the deiodinating activities. The deiodinating activities in hCASMCs and hASMCs were not inhibited by 1 mmol/L PTU and were demonstrated to have low Km for T4 and rT3. Furthermore, the deiodinating activities were decreased by the addition of thyroid hormones to the culture medium. Iodothyronine deiodinating activities in hCASMCs and hASMCs, therefore, have characteristics compatible with DII. Northern analysis using human DII cRNA probe clearly demonstrated the hybridization signals with
7.5 kb in size in hCASMCs and hASMCs.
The size of DII mRNA in hCASMCs and hASMCs was indistinguishable from
that in human thyroid gland.9
The expression of DII in both hCASMCs and hASMCs suggests the
ubiquitous expression of DII in human vascular SMCs. Although the
expression of DII mRNA in human heart and skeletal muscle has been
observed after the molecular cloning of human DII
cDNA,10 the present results
appear as the first demonstration of the expression of DII in human
vascular SMCs. DII activity is controlled by thyroid hormones at two levels. T4 and rT3 suppress DII activity mainly at the post-translational level through acceleration of the degradation rate of DII protein.20 Both T4 and rT3 are more potent in producing this effect than T3, suggesting that this effect does not require TRs. Recently, proteasomal degradation has been demonstrated to be involved in the post-translational regulation of DII activity by thyroid hormones.23 In contrast, T3 suppresses DII activity by decreasing DII mRNA without affecting its half-life, indicating that this effect is due to suppression of transcription of DII gene through TRs.21 Because the half-life of DII mRNA is 2 hours and that of DII enzyme is 40 minutes, the suppression of DII by thyroid hormones is very rapid whether the decrease in activity is induced by transcriptional or post-translational effects.21 In the present study, thyroid hormones inhibited DII mRNA expression, and the potency of the inhibitory effect was T3>T4>rT3. Although the deiodinating activity was also decreased by thyroid hormones, the potency of the inhibitory effect was T4>rT3>T3. These results suggest that T3 suppresses DII activity mainly at the pretranslational level, whereasT4 or rT3 suppresses DII activity largely at the post-translational level in hCASMCs and hASMCs, in agreement with previous observations for DII in other tissues and cells.14 20 21 22 The possible transcriptional regulation of DII by T3 is further supported by the presence of TR isoforms in hCASMCs and hASMCs demonstrated in the present study. Because DII expression in hCASMCs and hASMCs could be increased in the hypothyroid state, DII in human vascular SMCs might play a role in the protection of human vessels from local T3 deficiency in hypothyroidism.
In the present study, both DII activities and DII mRNA levels were rapidly stimulated by forskolin or (Bu)2cAMP in hCASMCs and hASMCs, suggesting the pretranslational regulation of DII expression by a cAMP-dependent mechanism. The rapid stimulation of DII mRNA and DII activity was also observed in human skeletal muscle cells, rat astrocytes, and pineal gland.14 24 25 Recently, a functional cAMP response element has been reported to be present in the human DII promoter region.26 Taken together, it is suggested that DII expression in hCASMCs and hASMCs is regulated by a cAMP-dependent mechanism at the transcriptional level.
It is generally accepted that calcium-dependent phosphorylation of myosin light chains initiates the contraction of vascular smooth muscle.27 Although the precise mechanisms underlying the action of endogenous vasodilator remain to be identified, it is postulated that cAMP-dependent protein kinase A inhibits calcium-dependent myosin light chain kinase.27 28 In the present study, it was demonstrated that intracellular accumulation of cAMP significantly stimulated DII expression in hCASMCs and hASMCs. Given that thyroid hormones have been reported to relax vascular SMCs directly,1 2 local production of T3 by DII might be another vasodilative mechanism mediated by cAMP regulatory cascade.
It has been reported that low serum selenium concentration increases the risk of ischemic heart disease.29 However, the mechanisms involved in the increased frequency of coronary heart disease in selenium deficiency are not known. Human DII cDNA contains in-frame TGA triplets that are not for termination codons but for the rare amino acid selenocysteine, which contains selenium.8 10 Because selenium is required to exert the full DII activity,24 one might speculate that local T3 production by DII in human vascular SMCs could be decreased by low serum selenium, which may be related to the increased risk of ischemic heart disease in selenium deficiency. Further studies are required to elucidate the pathophysiological roles of DII and selenium deficiency in atherosclerosis.
The physiological importance of intracellular thyroid hormone activation by DII has been clearly demonstrated in certain tissues. Adenohypophyseal T3 production by DII plays a role in feedback regulation of thyrotropin secretion by thyroid hormones.5 6 In the rat brown adipose tissue, the expression of uncoupling protein is regulated by locally generated T3, which is provided by DII.30 In the present study, TRs were demonstrated in hCASMCs and hASMCs by RT-PCR, suggesting that locally produced T3 by DII might play a role through TRs in vascular SMCs. Although the target genes induced by thyroid hormones in vascular SMCs are not known, it is of interest to study the possible role of locally produced T3 by DII in the regulation of vascular SMC–specific gene expression, which may be associated with SMC dedifferentiation that relates to atherosclerosis and ischemic heart disease.31 32
In summary, the present results demonstrate the expression of functional DII in human vascular SMCs, which may open novel perspectives on the roles of thyroid hormone metabolism in the pathophysiology of human vascular SMCs.
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Acknowledgments |
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This work was supported in part by Grant-in-Aid 09671024 (to M. Murakami) for scientific research from the Ministry of Education, Science, Sports and Culture of Japan. We are indebted to Drs Takayuki Ogiwara, Makoto Imamura, Yasuhiro Hosoi, Yuji Kamiya, Osamu Araki, Tadashi Morimura, and Tokuji Iriuchijima for their assistance and useful discussion.
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Footnotes |
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Original received May 9, 2000; resubmission received November 21, 2000; accepted December 7, 2000.
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References |
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 F. Galetta, F. Franzoni, P. Fallahi, L. Tocchini, L. Braccini, G. Santoro, and A. Antonelli Changes in heart rate variability and QT dispersion in patients with overt hypothyroidism Eur. J. Endocrinol., January 1, 2008; 158(1): 85 - 90. [Abstract] [Full Text] [PDF]
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 K. G. Moulakakis, D. P. Sokolis, D. N. Perrea, T. Dosios, I. Dontas, M. V. Poulakou, C. A. Dimitriou, G. Sandris, and P. E. Karayannacos The Mechanical Performance and Histomorphological Structure of the Descending Aorta in Hyperthyroidism Angiology, June 1, 2007; 58(3): 343 - 352. [Abstract] [PDF]
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D. Tiosano, L. Even, Z. Shen Orr, and Z. Hochberg Recombinant Thyrotropin in the Diagnosis of Congenital Hypothyroidism J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1434 - 1437. [Abstract] [Full Text] [PDF]
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 O. Gumieniak, T. S. Perlstein, J. S. Williams, P. N. Hopkins, N. J. Brown, B. A. Raby, and G. H. Williams Ala92 Type 2 Deiodinase Allele Increases Risk for the Development of Hypertension Hypertension, March 1, 2007; 49(3): 461 - 466. [Abstract] [Full Text] [PDF]
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J.-M. Fernandez-Real, A. Lopez-Bermejo, A. Castro, R. Casamitjana, and W. Ricart Thyroid Function Is Intrinsically Linked to Insulin Sensitivity and Endothelium-Dependent Vasodilation in Healthy Euthyroid Subjects J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3337 - 3343. [Abstract] [Full Text] [PDF]
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 K. Fukuyama, T. Ichiki, I. Imayama, H. Ohtsubo, H. Ono, Y. Hashiguchi, A. Takeshita, and K. Sunagawa Thyroid Hormone Inhibits Vascular Remodeling Through Suppression of cAMP Response Element Binding Protein Activity Arterioscler Thromb Vasc Biol, September 1, 2006; 26(9): 2049 - 2055. [Abstract] [Full Text] [PDF]
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O. Gumieniak, S. Hurwitz, T. S. Perlstein, U. C. Ngumezi, P. N. Hopkins, X. Jeunemaitre, and G. H. Williams Aggregation of High-Normal Thyroid-Stimulating Hormone in Hypertensive Families J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 5985 - 5990. [Abstract] [Full Text] [PDF]
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 Y. Sato, R. Nakamura, M. Satoh, K. Fujishita, S. Mori, S. Ishida, T. Yamaguchi, K. Inoue, T. Nagao, and Y. Ohno Thyroid Hormone Targets Matrix Gla Protein Gene Associated With Vascular Smooth Muscle Calcification Circ. Res., September 16, 2005; 97(6): 550 - 557. [Abstract] [Full Text] [PDF]
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 R. P. Peeters, A. W. van den Beld, H. Attalki, H. v. Toor, Y. B. de Rijke, G. G. J. M. Kuiper, S. W. J. Lamberts, J. A. M. J. L. Janssen, A. G. Uitterlinden, and T. J. Visser A new polymorphism in the type II deiodinase gene is associated with circulating thyroid hormone parameters Am J Physiol Endocrinol Metab, July 1, 2005; 289(1): E75 - E81. [Abstract] [Full Text] [PDF]
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T. Morimura, K. Tsunekawa, T. Kasahara, K. Seki, T. Ogiwara, M. Mori, and M. Murakami Expression of Type 2 Iodothyronine Deiodinase in Human Osteoblast Is Stimulated by Thyrotropin Endocrinology, April 1, 2005; 146(4): 2077 - 2084. [Abstract] [Full Text] [PDF]
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 A. Colantuoni, P. L. Marchiafava, D. Lapi, F. S. Forini, and G. Iervasi Effects of tetraiodothyronine and triiodothyronine on hamster cheek pouch microcirculation Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1931 - H1936. [Abstract] [Full Text] [PDF]
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S. Yasuzawa-Amano, N. Toyoda, A. Maeda, A. Kosaki, Y. Mori, T. Iwasaka, and M. Nishikawa Expression and Regulation of Type 2 Iodothyronine Deiodinase in Rat Aorta Media Endocrinology, December 1, 2004; 145(12): 5638 - 5645. [Abstract] [Full Text] [PDF]
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O. Gumieniak, T. S. Perlstein, P. N. Hopkins, N. J. Brown, L. J. Murphey, X. Jeunemaitre, N. K. Hollenberg, and G. H. Williams Thyroid Function and Blood Pressure Homeostasis in Euthyroid Subjects J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3455 - 3461. [Abstract] [Full Text] [PDF]
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F. Monzani, N. Caraccio, M. Kozakowa, A. Dardano, F. Vittone, A. Virdis, S. Taddei, C. Palombo, and E. Ferrannini Effect of Levothyroxine Replacement on Lipid Profile and Intima-Media Thickness in Subclinical Hypothyroidism: A Double-Blind, Placebo- Controlled Study J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2099 - 2106. [Abstract] [Full Text] [PDF]
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A. R. Cappola and P. W. Ladenson Hypothyroidism and Atherosclerosis J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2438 - 2444. [Full Text] [PDF]
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K. Fukuyama, T. Ichiki, K. Takeda, T. Tokunou, N. Iino, S. Masuda, M. Ishibashi, K. Egashira, H. Shimokawa, K. Hirano, et al. Downregulation of Vascular Angiotensin II Type 1 Receptor by Thyroid Hormone Hypertension, March 1, 2003; 41(3): 598 - 603. [Abstract] [Full Text] [PDF]
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K. Obuobie, J. Smith, L. M. Evans, R. John, J. S. Davies, and J. H. Lazarus Increased Central Arterial Stiffness in Hypothyroidism J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4662 - 4666. [Abstract] [Full Text] [PDF]
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E. Fommei and G. Iervasi The Role of Thyroid Hormone in Blood Pressure Homeostasis: Evidence from Short-Term Hypothyroidism in Humans J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 1996 - 2000. [Abstract] [Full Text] [PDF]
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 A. C. Bianco, D. Salvatore, B. Gereben, M. J. Berry, and P. R. Larsen Biochemistry, Cellular and Molecular Biology, and Physiological Roles of the Iodothyronine Selenodeiodinases Endocr. Rev., February 1, 2002; 23(1): 38 - 89. [Abstract] [Full Text] [PDF]
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I. Klein and K. Ojamaa Thyroid Hormone : Targeting the Vascular Smooth Muscle Cell Circ. Res., February 16, 2001; 88(3): 260 - 261. [Full Text] [PDF]
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