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(Circulation Research. 2001;88:260.)
© 2001 American Heart Association, Inc.

Editorial

Thyroid Hormone

Targeting the Vascular Smooth Muscle Cell

Irwin Klein, Kaie Ojamaa

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{at}nshs.edu

Key Words: thyroid hormone • vascular resistance • cardiovascular hemodynamics

	Introduction

Top Introduction References

 
Thyroid 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 calcium–activated 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 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 (10^-7 to 10^-10 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 plasma-membrane 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 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.).

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

Top Introduction References

 

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