Thyroid Hormone
2001; Lippincott Williams & Wilkins; Volume: 88; Issue: 3 Linguagem: Inglês
10.1161/01.res.88.3.260
ISSN1524-4571
Autores Tópico(s)Growth Hormone and Insulin-like Growth Factors
ResumoHomeCirculation ResearchVol. 88, No. 3Thyroid Hormone Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBThyroid Hormone Targeting the Vascular Smooth Muscle Cell Irwin Klein and Kaie Ojamaa Irwin KleinIrwin Klein 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. and Kaie OjamaaKaie 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. Originally published16 Feb 2001https://doi.org/10.1161/01.RES.88.3.260Circulation Research. 2001;88:260–261Thyroid 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.13Over 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).16 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.136 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.78The 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.1112 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.161617 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.1819Studies 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.181921The 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.1Drawing 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.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.This work was supported by National Institutes of Heath grants R01HL03775, HL56804 (to K.O.), and R01 HL58849 (to I.K.).FootnotesCorrespondence to Irwin Klein, MD, Chief, Division of Endocrinology, North Shore University Hospital, 300 Community Dr, Manhasset, NY 11030. E-mail [email protected] References 1 Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med.2001; 344:501–509.CrossrefMedlineGoogle Scholar2 Graettinger JS, Muenster JJ, Cheechia CS. A correlation of clinical and hemodynamic studies in patients with hypothyroidism. J Clin Invest.1958; 38:502–510.Google Scholar3 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.CrossrefMedlineGoogle Scholar4 St. Germain DL, Galton VA. The deiodinase family of selenoproteins. Thyroid.1997; 7:655–668.CrossrefMedlineGoogle Scholar5 Brent GA. The molecular basis of thyroid hormone action. N Engl J Med.1994; 331:847–854.CrossrefMedlineGoogle Scholar6 Dillmann WH. Biochemical basis of thyroid action in the heart. Am J Med.1990; 88:626–630.CrossrefMedlineGoogle Scholar7 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.Google Scholar8 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.CrossrefMedlineGoogle Scholar9 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.CrossrefMedlineGoogle Scholar10 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.CrossrefMedlineGoogle Scholar11 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.CrossrefMedlineGoogle Scholar12 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.CrossrefMedlineGoogle Scholar13 Ojamaa K, Klemperer JD, Klein I. Acute effects of thyroid hormone on vascular smooth muscle. Thyroid.1996; 6:505–512.CrossrefMedlineGoogle Scholar14 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.CrossrefMedlineGoogle Scholar15 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.CrossrefMedlineGoogle Scholar16 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.CrossrefMedlineGoogle Scholar17 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.CrossrefMedlineGoogle Scholar18 Ojamaa K, Kenessey A, Klein I. Thyroid hormone regulation of phospholamban phosphorylation in the rat heart. Endocrinology.2000; 141:2139–2144.CrossrefMedlineGoogle Scholar19 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.CrossrefMedlineGoogle Scholar20 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.CrossrefMedlineGoogle Scholar21 Chen W, Lah M, Robinson PJ, Kemp BE. Phosphorylation of phospholamban in aortic smooth muscle cells and heart by calcium/calmodulin-dependent protein kinase II. Cell Signal.1994; 6:617–630.CrossrefMedlineGoogle Scholar22 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.CrossrefMedlineGoogle Scholar23 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 cardiac-specific thyrotoxicosis. Endocrinology.2001; 142:13–20.CrossrefMedlineGoogle Scholar24 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-β-selective agonist GC-1 differentially affects plasma lipids and cardiac activity. Endocrinology.2000; 141:3057–3064.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Egan C, Greenberg J and Fahey T (2021) Endocrine Hypertensive Emergencies Endocrine Surgery Comprehensive Board Exam Guide, 10.1007/978-3-030-84737-1_42, (1013-1037), . Hashimoto G, Wada S, Yoshino F, Kuwashiro T, Yasaka M and Okada Y (2020) Case report: transient ischemic stroke caused by internal carotid artery occlusion due to compression by pituitary apoplexy and hemodynamic mechanism下垂体卒中による副腎不全で血行力学的に一過性脳虚血発作を発症した1例, Rinsho Shinkeigaku, 10.5692/clinicalneurol.cn-001372, 60:2, (146-151), . 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February 16, 2001Vol 88, Issue 3Article InformationMetrics © 2001 American Heart Association, Inc.https://doi.org/10.1161/01.RES.88.3.260 Originally publishedFebruary 16, 2001 Keywordscardiovascular hemodynamicsthyroid hormonevascular resistancePDF download Advertisement
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