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Thyroid Hormone
Targeting the Vascular Smooth Muscle Cell
Irwin Klein, Kaie Ojamaa

hyroid hormones (THs) exert marked effects on cardiac function that result from direct effects of the
hormones on the cardiac myocyte as well as effects on
the peripheral vasculature.1 The latter effect is best demonstrated by the characteristically high systemic vascular resistance (SVR) observed in patients (and experimental animals)
with hypothyroidism, which is rapidly reversed with TH
treatment.2 Hyperthyroidism produces a marked decrease in
SVR, which in turn facilitates an increase in cardiac output
and augments peripheral blood flow characteristic of this
disease state.1,3
Over 85% of the TH synthesized and released from the
thyroid gland is in the form of tetraiodothyronine (thyroxine,
T4). Conversion of T4 to the biologically active form of the
hormone, triiodothyronine (T3), occurs by 5 monodeiodination (type I 5 deiodinase) primarily in the liver and kidney
and, to a smaller extent, by type II 5 deiodinase activity in
the pituitary and brain.4 In most tissues, the mechanism of TH
biological action occurs by the entry of T3 into the cell by
facilitated transport and the binding of T3 to specific nuclear
T3 receptors (TRs), which regulate transcription of target
genes.5 In the heart, these genes include contractile proteins
(myosin heavy chains) as well as calcium transport/regulatory
proteins (sarcoplasmic reticulum calciumactivated ATPase
and phospholamban).1,6 Nuclear TRs, which belong to the
steroid superfamily of transcription factors, bind T3 with
much greater affinity than T4 and can either positively or
negatively regulate transcriptional activity, depending on the
presence or absence of T3 and a T3-responsive DNA element.5
Thus, the inotropic effect of TH on the cardiac myocyte is
primarily determined by its ability to alter cellular phenotype.1,3,6 In addition, nongenomic actions of T3 have been
identified, in which T3 regulates the ion flux of plasma
membrane ion channels that in turn determine membrane
potential, depolarization characteristics, and contractile
activity.7,8
The cardiovascular hemodynamic effects of TH cannot be
explained solely by the positive inotropic and lusitropic
effects of T3 on the heart. As previously studied, the fall in
SVR promotes and facilitates the increase in cardiac output of
The opinions expressed in this editorial are not necessarily those of the
editors or of the American Heart Association.
From the Department of Medicine, Division of Endocrinology, North
Shore University Hospital, Manhasset, NY, and Department of Cell
Biology, New York University School of Medicine, New York, NY.
Correspondence to Irwin Klein, MD, Chief, Division of Endocrinology, North Shore University Hospital, 300 Community Dr, Manhasset,
NY 11030. E-mail iklein@nshs.edu
(Circ Res. 2001;88:260-261.)
2001 American Heart Association, Inc.
Circulation Research is available at http://www.circresaha.org

both the normal and the pathological failing heart.1 This has
been clearly demonstrated in patients receiving short-term T3
infusion after cardiac surgery9 and in patients with advanced
congestive heart failure,10 in whom the rise in cardiac index
was linked to the fall in SVR. In experimental animals and
human studies, T3 was shown to enhance ventriculoarterial
coupling and augment left ventricular work with a lower
increment in left ventricular oxygen consumption compared
with that resulting from inotropic agents.11,12 Given these
observations, the mechanism by which TH promotes a fall in
vascular resistance gains clinical significance.
Studies using vascular smooth muscle (VSM) cells isolated
from rat aorta and cultured on a deformable matrix demonstrated that exposure to T3 caused these cells to relax rapidly,
suggesting a nongenomic mechanism of action.13 This effect
was selective for T3 and was not mediated by cAMP or nitric
oxide. Hormone-binding studies using VSM cell plasma
membrane showed that T3 bound with an 100-fold greater
affinity than T4.13 While both T3 and T4 caused relaxation of
preconstricted isolated skeletal muscle resistance arterioles
within 20 minutes after exposure to hormone,14 T3 was more
effective at all concentrations studied (107 to 1010 mol/L).
This difference between the vasodilatory effectiveness of T4
and T3 on VSM may be resolved by the observations of
Mizuma et al,15 who have shown in this issue of Circulation
Research the presence of an iodothyronine deiodinase in
human VSM cells. They report that this deiodinase activity is
characteristic of a type II enzyme (brain and pituitary), such
that the enzymatic activity is regulated by T4 whereas its
expression is transcriptionally regulated by cAMP and T3.
The presence of this enzyme in human vascular cells suggests
that VSM cells are physiological targets for the action of TH,
and that VSM can convert T4 to the active hormone T3 to
promote cellular activity.
The identification of four thyroid hormone receptor mRNA
isoforms in both human aortic and coronary VSM confirms
previous reports of TR mRNAs in rat primary VSM cells and
points to a classic genomic action of T3 in these cells.13 This
implies that in addition to the nongenomic effects of T3 on
vascular tone, T3 may determine VSM contractility by regulating its phenotype through classic nuclear transcription
mechanisms. However, as acknowledged by Mizuma et al,15
the target genes for T3 action in the VSM cell remain
unknown. It is interesting to speculate that T3 target genes in
VSM cells may be similar to those previously described in the
cardiac myocyte, which include the sarcoplasmic reticulum
Ca2-activated ATPase, phospholamban (PLB), and plasmamembrane ion channels, such as voltage-gated Kv1.5 and
Kv4.2, Na-Ca2 exchanger, and Na-K-ATPase.1,6,16,17 The
role of T3 in regulating protein phosphorylation of these

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Klein and Ojamaa

calcium channels/transporters may additionally modulate
VSM contractility by changes in SR and sarcolemmal ion
flux.18,19
Studies using genetic ablation of the PLB gene showed
alterations in aortic smooth muscle cell contractility, suggesting a possible molecular mechanism by which TH regulates
SVR.20 If PLB expression in VSM is negatively regulated by
T3, as it is in the cardiac myocyte,17 then TH could promote
cell relaxation in a manner similar to the lusitropic effect
characteristic of the myocardium.3 Furthermore, TH acting
through either increased cAMP-dependent protein kinase or
calcium-calmodulin dependent protein kinase activity to increase PLB phosphorylation in VSM, as has been reported in
the heart, may provide a mechanism by which T3 regulates
cellular relaxation.18,19,21
The presence of type II 5 monodeiodinase in VSM
additionally raises the question of how this system may
function in the disease states of atherosclerosis and hypertension. Although a recent study22 has shown accelerated atherosclerotic disease in patients with even mild hypothyroidism, the long-held association between hypothyroidism and
hypercholesterolemia probably underlies much of this pathology. The finding that as many as 25% of hypothyroid patients
have diastolic hypertension with an increased SVR points to
an important role of TH and its metabolites in the normal
regulation of blood pressure.1
Drawing from the study by Mizuma et al15 and using
methodology recently reported by Pachucki et al,23 who
overexpressed the type II deiodinase in the cardiac myocyte,
it may be possible to target TH to the VSM. This approach
may allow increased conversion of T4 to T3 in the VSM cell,
thereby increasing the cellular action of the hormone and
providing a novel mechanism for regulating SVR and blood
pressure. Recent reports have studied the ability of TH
analogues to lower plasma lipids without concomitant
changes in cardiovascular hemodynamics.24 Conversely, with
the evidence that VSM is a target for TH action, a TH
analogue that acts selectively at the VSM cell to promote
vasodilatation may serve as a novel class of antihypertensive
agents.

Acknowledgments
This work was supported by National Institutes of Heath grants
R01HL03775, HL56804 (to K.O.), and R01 HL58849 (to I.K.).

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KEY WORDS: thyroid hormone
hemodynamics

vascular resistance

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cardiovascular

Thyroid Hormone: Targeting the Vascular Smooth Muscle Cell

Irwin Klein and Kaie Ojamaa
Circ Res. 2001;88:260-261
doi: 10.1161/01.RES.88.3.260
Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2001 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7330. Online ISSN: 1524-4571

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