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See related article, pages 313–318 Thyroid Hormone Targeting the Vascular Smooth Muscle Cell Irwin Klein, Kaie Ojamaa T Downloaded from http://circres.ahajournals.org/ by guest on May 4, 2017 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 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 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 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 [email protected] (Circ Res. 2001;88:260-261.) © 2001 American Heart Association, Inc. Circulation Research is available at http://www.circresaha.org 260 Klein and Ojamaa Downloaded from http://circres.ahajournals.org/ by guest on May 4, 2017 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.). References 1. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med. 2001;344:501–509. 2. Graettinger JS, Muenster JJ, Cheechia CS. A correlation of clinical and hemodynamic studies in patients with hypothyroidism. J Clin Invest. 1958;38:502–510. 3. Mintz G, Pizzarello R, Klein I. Enhanced left ventricular diastolic function in hyperthyroidism: noninvasive assessment and response to treatment. J Clin Endocrinol Metab. 1991;73:146 –150. 4. St. Germain DL, Galton VA. The deiodinase family of selenoproteins. Thyroid. 1997;7:655– 668. T3 and Blood Pressure 261 5. Brent GA. The molecular basis of thyroid hormone action. N Engl J Med. 1994;331:847– 854. 6. Dillmann WH. Biochemical basis of thyroid action in the heart. Am J Med. 1990;88:626 – 630. 7. Sun Z-Q, Ojamaa K, Coetzee WA, Artman M, Klein I. Effects of thyroid hormone on action potential and repolarizing currents in rat ventricular myocytes. Am J Physiol. 2000;278:E3022–E3027. 8. Sakaguchi Y, Cui G, Sen L. Acute effects of thyroid hormone on inward rectifier potassium channel currents in guinea pig ventricular myocytes. Endocrinology. 1996;137:4744 – 4751. 9. Klemperer J, Klein I, Gomez M, Helm RE, Ojamaa K, Thomas SJ, Isom OW, Krieger K. Effects of thyroid hormone supplementation in cardiac surgery. N Engl J Med. 1995;333:1522–1527. 10. Hamilton MA, Stevenson LW, Fonarow GC, Steimle A, Goldhaber JI, Child JS, Chopra IJ, Moriguchi JD, Hage A. Safety and hemodynamic effects of intravenous triiodothyronine in advanced congestive heart failure. Am J Cardiol. 1998;81:443– 447. 11. DiPierro FV, Bavaria JE, Lankford EB, Polidori DJ, Acker MA, Streicher JT, Gardner TJ. Triiodothyronine optimizes sheep ventriculoarterial coupling for work efficiency. Ann Thorac Surg. 1996;62:662– 669. 12. Bengel FM, Nekolla S, Ziegler SI, Schwaiger M. Effect of thyroid hormones on cardiac function and oxidative metabolism assessed noninvasively by positron emission tomography and magnetic resonance imaging. J Clin Endo Metab. 2000;85:1822–1827. 13. Ojamaa K, Klemperer JD, Klein I. Acute effects of thyroid hormone on vascular smooth muscle. Thyroid. 1996;6:505–512. 14. Park KW, Dai HB, Ojamaa K, Lowenstein E, Klein I, Sellke FW. The direct vasomotor effect of thyroid hormones on rat skeletal muscle resistance arteries. Anesth Analg. 1997;85:734 –738. 15. Mizuma H, Murakami M, Mori M. Thyroid hormone activation in human vascular smooth muscle cells: expression of type II iodothyronine deiodinase. Circ Res. 2001;88:313-318. 16. Ojamaa K, Sabet A, Kenessey A, Shenoy R, Klein I. Regulation of rat cardiac Kv1.5 gene expression by thyroid hormone is a rapid and chamber specific. Endocrinology. 1999;140:3170 –3176. 17. Kiss E, Jakab G, Kranias EG, Edes I. Thyroid hormone-induced alterations in phospholamban protein expression: regulatory effects on sarcoplasmic reticulum Ca2⫹ transport and myocardial relaxation. Circ Res. 1994;75:245–251. 18. Ojamaa K, Kenessey A, Klein I. Thyroid hormone regulation of phospholamban phosphorylation in the rat heart. Endocrinology. 2000;141: 2139 –2144. 19. Karczewski P, Hendrischke T, Wolf, Morano I, Bartel S, Schrader J. Phosphorylation of phospholamban correlates with relaxation of coronary artery induced by nitric oxide, adenosine, and prostacyclin in the pig. J Cell Biochem. 1998;70:49 –59. 20. Paul RJ. The role of phospholamban and SERCA3 in regulation of smooth muscle-endothelial cell signalling mechanisms: evidence from gene-ablated mice. Acta Physiol Scand. 1998;164:589 –597. 21. Chen W, Lah M, Robinson PJ, Kemp BE. Phosphorylation of phospholamban in aortic smooth muscle cells and heart by calcium/calmodulindependent protein kinase II. Cell Signal. 1994;6:617– 630. 22. Hak AE, Pols HAP, Visser TJ, Drexhage HA, Hofman A, Witteman JC. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intern Med. 2000;132:270 –278. 23. Pachucki J, Hopkins J, Peeters R, Tu H, Carvalho SD, Kaulbach H, Abel ED, Wondisford FE, Ingwall JS, Larsen PR. Type II iodothyronine deiodinase transgene expression in the mouse heart causes cardiacspecific thyrotoxicosis. Endocrinology. 2001;142:13–20. 24. Trost SU, Swanson E, Gloss B, Wang-Iverson DB, Zhang H, Volodarsky T, Grover GJ, Baxter JD, Chiellini G, Scanlan TS, Dillmann WH. The thyroid hormone receptor--selective agonist GC-1 differentially affects plasma lipids and cardiac activity. Endocrinology. 2000;141:3057–3064. KEY WORDS: thyroid hormone hemodynamics 䡲 vascular resistance 䡲 cardiovascular Thyroid Hormone: Targeting the Vascular Smooth Muscle Cell Irwin Klein and Kaie Ojamaa Downloaded from http://circres.ahajournals.org/ by guest on May 4, 2017 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. 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