Review Article The Emerging Role of TR 1 in Cardiac Repair ...

Review ArticleThe Emerging Role of TR1205721 in Cardiac RepairPotential Therapeutic Implications

Constantinos Pantos and Iordanis Mourouzis

Department of Pharmacology University of Athens 75 Mikras Asias Avenue Goudi 11527 Athens Greece

Correspondence should be addressed to Constantinos Pantos cpantosmeduoagr

Received 8 November 2013 Accepted 31 December 2013 Published 9 February 2014

Academic Editor Neelam Khaper

Copyright copy 2014 C Pantos and I Mourouzis This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Thyroid hormone (TH) is critical for adapting living organisms to environmental stress Plasma circulating tri-iodothyronine (T3)levels drop in most disease states and are associated with increased oxidative stress In this context T3 levels in plasma appear to bean independent determinant for the recovery of cardiac function after myocardial infarction in patientsThyroid hormone receptor1205721 (TR1205721) seems to be crucial in this response TR1205721 accumulates to cell nucleus upon activation of stress induced growth kinasesignaling Furthermore overexpression of nuclear TR1205721 in cardiomyocytes can result in pathological or physiological growth (dualaction) in absence or presence of its ligand respectively Accordingly inactivation of TR1205721 receptor prevents reactive hypertrophyafter myocardial infarction and results in heart failure with increased phospholamban (PLB) expression and marked activationof p38MAPK In line with this evidence TH is shown to limit ischemiareperfusion injury and convert pathologic to physiologicgrowth after myocardial infarction via TR1205721 receptor TR1205721 receptor may prove to be a novel pharmacological target for cardiacrepair regeneration therapies

1 Introduction

Adaptation to the environmental oxygen variations wasan evolutionary challenge and allowed life to evolve inearth Transition from low to high oxygen environmentscan increase oxidative stress and result in tissue dam-age However living organisms evolved from aquatic toterrestrial environments by developing mechanisms thatenabled adaptation to changes in environmental oxygenThese mechanisms have been evolutionary conserved inmammals allowing mammalian birth to oxygen rich envi-ronment or implicated in freeze tolerance and arousal fromhibernation [1] Understanding the molecular basis of theadaptive responses of living organisms to stress may be ofphysiological relevance in the therapy of diseases In thiscontext recent experimental and clinical evidence shows thatthyroid hormone (TH) may be critical in stress responseand low TH in diseased states is associated with increasedoxidative stress [2 3] With this evidence in mind thisreview highlights the role of thyroid hormone signaling andparticularly of thyroid hormone receptor alpha1 (TR1205721) incardiac recovery following myocardial injury

2 Adaptation to Environmental StressThe Role of Thyroid Hormone (TH)

Amphibian metamorphosis is the most striking paradigmof adaptation to oxygen rich environment This biologicalprocess is entirely dependent on TH TH is low duringembryonic and early larva development and increases aslarva approaches metamorphosis A similar developmentalTH secretion pattern is observed in most species and inhumans [4] Furthermore distinct changes in deiodinasesand thyroid hormone receptors (TRs) expression occur andthus a single hormone can coordinate responses amongdifferent cell types and regulate the temporal sequence ofremodeling events during amphibian metamorphosis Moreimportantly TH can critically determine the amphibianphenotype (low oxygen aquatic versus high oxygen andterrestrial habitats) Thus in salamanders low TH resultsin permanent aquatic habitats delayed metamorphic timingand large body size whereas high TH has opposite effects [4]see Figure 1

Environmental stress appears to cause changes in thepattern of TH secretion similar to that observed in the early

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2014 Article ID 481482 8 pageshttpdxdoiorg1011552014481482

2 Oxidative Medicine and Cellular Longevity

Terrestrial adult

Metamorph

Aquatic adult

Paedomorph

Aquatic larva

Thyroid hormone

Genesenvironment

(+) (minus)

Figure 1 Critical levels of thyroid hormone (TH) induce metamorphosis in salamanders Low TH can adapt salamander to low oxygenaquatic environment by inducing growth with embryonic characteristics Addition of TH allows adaptation to terrestrial life and completesmetamorphosis Analogies seem to exist in mammals with TH to determine the phenotypic characteristics of the myocardium (pathologicalversus physiological growth) after ischemic events Evolutionary conserved mechanisms of adaptation may be the basis for cardiac repair(Permission by Johnson and Voss [4])

embryonic stagesThis response is likely to be part of an adap-tive response of the living organism to environmental stressThus exposure of air breathing perch to water-born keroseneresulted in low TH and unfavorable metabolic changes whilethe administration of TH reversed this response [5] Alongthis line cold stunning in sea turtles resulted in undetectablethyroid hormone levels and recovery induced by rewarmingwas associated with restoration of TH levels [6] Similarlyin humans TH levels decline after various stresses includingischemia infection and organ failure but the physiologicalrelevance of this response in regard to post-stress adaptationremains largely unknown [7 8]

3 TH Is Critical for the Recovery afterMyocardial Injury

Adecline in T3 levels occurswithin 48 hours(h) aftermyocar-dial infarction (AMI) or 6ndash24 h after cardiac surgery [9 10]Low T3 syndrome is present in nearly 20 of patients withAMI despite primary percutaneous coronary intervention(PCI) Low fT3 levels are associated with lower survivalrate particularly in patients with age less than 75 years [11]indicating that TH may have a role in adapting the heart tomyocardial injury In fact a link of TH to cardiac recoveryafter myocardial infarction has been recently established inhumans and in experimental studies

In a series of patients with AMI and primary PCI leftventricular ejection fraction (LVEF) 48 hours after theindex event was strongly correlated with T3 and not T4 levelsin plasma Furthermore at 6 months recovery of cardiacfunction was correlated with T3 plasma levels and T3 wasshown to be an independent determinant of LVEF recovery[12]

In accordance with this clinical evidence acute T3(and not T4) administration after ischemiareperfusion in

isolated rat hearts resulted in significant improvement ofpostischemic recovery of function [13 14] Furthermorein an experimental model of coronary ligation in micecardiac function was significantly decreased and this wasassociated with a marked decline in T3 levels in plasma T3replacement therapy significantly improved the recovery ofcardiac function [15 16]

On the basis of these data it appears that the active T3 andnot T4 is critical for the response to stress In fact T4 therapyin patients with euthyroid syndrome due to severe illness wasnot shown to be beneficial [17 18]

4 TR1205721 Receptor and Its Physiologic Actions

T3 the active form of TH exerts many of its actions throughits receptors (TRs) TR1205721 TR1205722 TR1205731 and TR1205732 TRswith the exception of TR1205732 are expressed in all tissues andthe pattern of expression varies in different types of tissues[19] TR1205721 is predominantly expressed in the myocardiumand regulates important genes related to cell differentiationand growth contractile function pacemaker activity andconduction [20ndash22]

The importance of TH in organ maturation duringdevelopment and its implication in cell differentiation haslong been recognizedThis unique action seems to be of phys-iological relevance in stem cell biology and cancer [23 24] T3can promote differentiation of human pluripotent stem cellderived cardiomyocytes (hips-CM) [23] and glioma tumorcell lines [24] The implication of TR1205721 in cell differentiationis shown in embryonic myoblast cultures (H9c2) whichis considered a suitable model to study cell differentiationMaturation of H9c2 is TH dependent process [25 26] TR1205721expression is increased in parallel with the intracellularT3 at the stage of cell differentiation and pharmacologicalinactivation of TR1205721 significantly delays cardiac myoblast

Oxidative Medicine and Cellular Longevity 3

maturation [27] Along this line TR1205721 is shown to playa critical role in pancreatic 120573-cell replication and in theexpansion of the 120573-cell mass during postnatal development[28]

T3 can induce physiologic growth and this action involvesthe activation of PI3 KAktmTOR pathway T3 regulates thispathway by the interaction of the cytosol-localized TR1205721 withthe p85120572 subunit of PI3 K [29 30]

TR1205721 appears to be required to repress basal expression of120573-isoform of myosin heavy chain (120573-MHC) and T3 induced120573-MHC repression [31] Deletion of TR1205721 results in lowerlevels of 120572-MHC and SERCA mRNA [32] whereas phos-pholamban (PLB) expression is greater in the myocardiumof animals with mutated TR1205721 [33] TR1205721 directly bindsat the PLB promoter region T3 can trigger alterations incovalent histone modifications at the PLB promoter whichare associated with gene silencing with lower histone H3acetylation and histone H3 lysine 4 methylation [34] In linewith this evidence contractile dysfunction is a consistentobservation in all studies using animals with mutated ordeleted TR1205721 receptor [32 33]

TH regulates the transcription of pacemaker channelgenes such asHCN2 andHCN4 and this action involves TR1205721receptor [32] Deletion of TR1205721 results in bradycardia [32 35]TR1205721 is also shown to bind to an element of rat connexin43 promoter region which may be of physiological relevanceregarding electrical conduction [36]

TH can control glucose metabolism in the heart viaTR1205721 receptor Thus glucose utilization in the myocardiumis impaired in mice with mutated TR1205721 [37] Furthermorepharmacological inhibition of TR1205721 in rats resulted inincreased glycogen content in the myocardium [38]

TR1205721 is the predominant TR isoform in mouse coronarysmooth muscle cells (SMCs) and seems to have a regulatoryrole in the coronary artery contractile function CoronarySMCs from TR1205721 knock-out mice exhibit a significantdecrease in K+ channel activity Furthermore in those arter-ies vascular contraction is significantly enhanced [39]

Collectively it appears that TR1205721 has a regulatory role incardiac homeostasis and thus it is likely to be implicated inthe pathophysiology of cardiac disease This hypothesis hasnot until recently been explored

5 TR1205721 and Response ofthe Myocardium to Stress

The potential link of TH signaling to cardiac pathologyand particularly of TR1205721 receptor has been investigated inseveral studies withmuch controversy surrounding this issueInitial observations showed that TR1205721 mRNA is suppressedin left ventricles of patients with dilated cardiomyopathyin comparison with donor hearts [40] Accordingly TR1205721mRNA was found to be downregulated in the myocardiumof animals with ascending aortic constriction (TAC) [41 42]Furthermore TR1205721 mRNA was found to be suppressed afterphenylephrine (PE an alpha1-adrenergic agonist which is astimulus for pathologic growth) administration in neonatalcardiomyocytes [42] Overexpression of TR1205721 was shown to

reverse PE and TAC induced hypertrophic phenotype [4142] However this was not a consistent result in all studiesOverexpression of TR1205721 resulted in physiologic growth inone study [42] and pathologic growth in another study [43]Here it should be noted that in all those studies TR1205721 wasmeasured at mRNA level and not at protein level TR1205721protein expression was measured in subsequent studies incardiac specimens from patients with heart failure TR1205721 wasfound to be upregulated in one study [44] and downregulatedin another study [45] To add to the controversy TR1205721was shown to be overexpressed [46] or downregulated [47]in animal models of cardiac remodeling after myocardialinfarction On the basis of this conflicting evidence it isconceivable that clear conclusions cannot be drawn regardingpotential role of TR1205721 receptor in stressed myocardium

6 TR1205721 A Component of Stress InducedGrowth Signaling Pathways

Recent experimental studies have shed more light regardingthe role of TR1205721 in the response of the myocardium to stressand seem to resolve the controversy Thus a distinct patternof TR1205721 expression is shown to occur in the myocardiumafter acute myocardial infarction indicating a potential linkof TR1205721 to reactive cardiac hypertrophy TR1205721 (nuclearpart) was shown to be upregulated during the developmentof compensatory pathological hypertrophy in parallel witha greater activation of ERK and mTOR growth signalingConsequently TR1205721 declines along with a marked reductionin ERK and mTOR signaling activation on the transitionof pathological hypertrophy to congestive heart failure [48]Studies in cultured cardiomyocytes further showed that TR1205721receptor can be overexpressed in cell nucleus in responseto growth stimuli such as phenylephrine (PE) [27] Thisresponse was shown to be due to redistribution of TR1205721from cytosol to nucleus This process is regulated via ERKandmTOR signaling In those experiments overexpression ofTR1205721 receptor was shown to be associated with pathologicalgrowth (with dominant 120573-MHC expression) only in theabsence of TH in culture medium Figure 2 Furthermoreinhibition of ERK andmTOR signaling abolished TR1205721 accu-mulation in cell nucleus and prevented the development ofPE induced pathological growth see Figure 2 This responsecould be elicited by 1205721 adrenergic and not 1205732-adrenergicstimulation (unpublished data) while treatment of neonatalcells with inflammatory mediators such as TNF-alpha hadno effect on nuclear TR1205721 expression [49] Collectively thesedata provide substantial evidence that stress induced accu-mulation of TR1205721 in cell nucleus may be an important com-ponent of the mechanisms involved in compensatory growthresponse after myocardial infarction This hypothesis hasrecently been tested in studies in which debutyl-dronedarone(DBD) a TR1205721 inhibitor was administered after AMI inmice[50] DBD treatment was shown to reduce recovery of cardiacfunction prevent compensatory hypertrophy increase PLBexpression (TR1205721 responsive gene) and result in markedactivation of p38 MAPK [51] The latter may be of importantphysiological relevance Stress induced activation of p38


140

120

100

80

60

40

20

0

Myosin heavy chain isoform expressionlowast

lowastlowast

120572-MHC

AB

CD

120573-MHC

Nontreated neonatal cardiomyocytes

treated cells(overexpressing TR1205721

in nucleus)

treated cells(not overexpressing TR1205721

in nucleus)


in nucleus)

(A)

(B)

(C)

(D)

PE minus T3

PE minus T3 + PD

PE + T3

Figure 2 Thyroid hormone (TH) determines the growth responseto stress Stress induced (by PE a growth stimulus) overexpressionof TR1205721 in neonatal cardiomyocytes resulted in pathologic growthwith dominant beta-MHC expression only in the absence of THin the cultured medium (PE-T3) (B) This response was abolishedafter PD98059 administration (an ERK inhibitor) which preventsPE induced TR1205721 accumulation in nucleus (PE-T3 + PD) (C) In thepresence of TH in culturedmedium PE inducedTR1205721 accumulationin nucleus resulted in physiologic growth with suppressed beta-MHC and increased alpha-MHC (PE + T3) (D) lowast119875 lt 005 versusA lowastlowast119875 lt 005 versus B

119875 lt 005 versus A B and C PE =phenylephrine MHC = myosin heavy chain

MAPK can cause apoptosis low proliferative activity andimpaired tissue repairregeneration [52ndash54]

7 TR1205721 A Molecular Switch to ConvertPathologic to Physiologic Growth

The potential link of TR1205721 to growth response has beenrevealed in neonatal cardiomyocytes cultures in whichphenylephrine (PE) was administered in the presence orabsence of TH in culture medium In this series of exper-iments PE administration resulted in increased nuclearTR1205721 content and in pathologic growth (dominant 120573-MHCexpression) in the absence of T3 and physiologic growth inthe presence of T3 in culture medium [27] see Figure 2Thus TR1205721 receptor appears to act as a molecular switchto convert pathologic to physiologic growth Consistent withthis evidence TH replacement therapy following myocardialinfarction in mice resulted in compensatory hypertrophywith adult pattern of myosin isoform expression [16] Fur-thermore increased expression of liganded TR1205721 in themyocardium after physical training in patients with heartfailure and mechanical support devices was associated withupregulation of physiologic growth kinase signaling [55]Similarly TH restoredmyelination and clinical recovery afterintraventricular hemorrhage by converting the unligandedaporeceptor TR1205721 to holoreceptor [56]

8 TR1205721 and IschemiaReperfusion Injury

TH has long been considered to be detrimental for theresponse of themyocardium to ischemic stress However thislong standing belief has been challenged over the past yearsIn fact in a series of studies using isolated rat heart modelsof ischemiareperfusion TH pretreatment was shown to bebeneficial and mimic the effect of ischemic preconditioning[57] Furthermore T3 (and not T4) administration at reper-fusion suppressed apoptosis limited necrosis and improvedpostischemic recovery of function [13 14] Similarly THtreatment after myocardial infarction limited infarct size [58]and reduced apoptosis in the border zone of the infarctedarea [59] The reparative effect of TH seems to be mediatedvia activation of prosurvival signaling pathways Thus THactivates Akt [16 59ndash61] and regulates PKC isoforms expres-sion [62 63] HSP70 expression [64] and HSP27 expressionand phosphorylation and translocation [65] FurthermoreTH suppresses ischemiareperfusion induced p38MAPK andJNK activation [14 66] TH reparative action is shown to bemediated via TR1205721 receptor [13] Here it is worthmentioningthat T3 can also limit streptozotocin (STZ) induced betapancreatic cell apoptosis via TR1205721 receptorThus TH admin-istration in STZ treated animals with myocardial infarctionresulted in increased insulin levels in plasma and significantimprovement of the postischemic cardiac dysfunction [61]

9 Clinical and Therapeutic Implications

Reperfusion injury and postischemic cardiac remodelingremain still a therapeutic challenge in the managementof patients with heart disease [67 68] The discovery ofnovel pharmacological targets such as TR1205721 receptor maybe of important clinical and therapeutic relevance TH


Cardiac injury

Pathologicremodeling

Physiologicremodeling

Heart failure Cardiac repair

Activation of growthkinase signaling

TR1205721

darrT3

uarrTR1205721

darrT3 T3uarrT3

Figure 3 Schematic showing TR1205721 involvement in the response ofthe myocardial tissue to injury

has already been tried in clinical settings of controlledischemiareperfusion such as CABG or heart donors preser-vation Thus T3 treatment postoperatively limited reper-fusion injury and improved haemodynamics in patientsundergoing CABG [69] Furthermore T3 treatment initiatedone week before GABG resulted in improved cardiac indexand reduced requirements of inotropes [70] Similarly THhas been used in heart donors to increase the probabilityof success in donor organ transplantation However a clearbenefit of this treatment has not been demonstrated [71]This may be due to the fact that most of the patients werereceiving T4 instead of the active T3 and TH treatmentwas used in nonischemic stable donor hearts In fact whenT3 was administered in a series of 22 unstable (ischemic)heart donors (considered unsuitable for transplantation) 17of those patients progressed to successful transplantation[72] Here it should be noted that TH was shown to facilitaterecovery in patients with end-stage heart failure andmechan-ical support devices [73]

On the basis of these preliminary clinical data large-scaleclinical trials may be needed to demonstrate the beneficialeffect of TH in clinical settings of ischemiareperfusionFurthermore the recognition that TH canmediate importantphysiological and pharmacological actions via TR1205721 receptormay allow selective pharmacological manipulation of THsignaling via TR1205721 agonists Currently only TR120573 analogshave been synthesized to control cholesterol metabolismHowever a chemical compound (CO23) which is assumedto be a TR1205721 selective agonist has recently been synthesized

This compound although it was shown to be selective forTR1205721 receptor in amphibian models it lost its selectivity inrat [74 75] This may be due to differences in TR expressionin developing and mature tissues This issue is of importanttherapeutic relevance and merits further investigation

10 Concluding Remarks

TH is long known to be critical in organmaturation and regu-lation ofmetabolismHowever recent accumulating evidenceshows that TH is crucial for the response of living organismsto environmental stress In particular TR1205721 receptor seemsto be an important determinant for the reactive growthresponse which occurs after myocardial injury TR1205721 can actas a molecular switch to convert pathological to physiologicgrowth see Figure 3 Due to this dual action TH via TR1205721receptor can limit myocardial injury and rebuild the injuredmyocardium It is likely that TR1205721 receptormay prove a novelpharmacological target for cardiac repairregeneration

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] K B Storey ldquoAdventures in oxygen metabolismrdquo ComparativeBiochemistry and Physiology B vol 139 no 3 pp 359ndash369 2004

[2] A Mancini G M Corbo A Gaballo et al ldquoRelationshipbetween plasma antioxidants and thyroid hormones in chronicobstructive pulmonary diseaserdquo Experimental and ClinicalEndocrinology amp Diabetes vol 120 no 10 pp 623ndash628 2013

[3] A Mancini S Raimondo C di Segni et al ldquoThyroid hor-mones and antioxidant systems focus on oxidative stress incardiovascular and pulmonary diseasesrdquo International Journalof Molecular Sciences vol 14 no 12 pp 23893ndash23909 2013

[4] C K Johnson and S R Voss ldquoSalamander paedomorphosislinking thyroid hormone to life history and life cycle evolutionrdquoCurrent Topics in Developmental Biology vol 103 pp 229ndash2582013

[5] V S Peter E K Joshua S E W Bonga and M C SPeter ldquoMetabolic and thyroidal response in air-breathing perch(Anabas testudineus) to water-borne kerosenerdquo General andComparative Endocrinology vol 152 no 2-3 pp 198ndash205 2007

[6] K E Hunt C Innis and R M Rolland ldquoCorticosteroneand thyroxine in cold-stunned Kemprsquos ridley sea turtles (Lep-idochelys kempii)rdquo Journal of Zoo andWildlife Medicine vol 43no 3 pp 479ndash493 2012

[7] L J de Groot ldquoNon-thyroidal illness syndrome is a manifesta-tion of hypothalamic-pituitary dysfunction and in view of cur-rent evidence should be treated with appropriate replacementtherapiesrdquo Critical Care Clinics vol 22 no 1 pp 57ndash86 2006

[8] J E Mitchell A S Hellkamp D B Mark et al ldquoThyroidfunction in heart failure and impact onmortalityrdquoHeart Failurevol 1 no 1 pp 48ndash55 2013

[9] B Eber M Schumacher W Langsteger et al ldquoChanges inthyroid hormone parameters after acutemyocardial infarctionrdquoCardiology vol 86 no 2 pp 152ndash156 1995


[10] FWHolland II P S Brown Jr B DWeintraub andR E ClarkldquoCardiopulmonary bypass and thyroid function a lsquoeuthyroidsick syndromersquordquo The Annals of Thoracic Surgery vol 52 no 1pp 46ndash50 1991

[11] C Lazzeri A Sori C Picariello M Chiostri G F Gensiniand S Valente ldquoNonthyroidal illness syndrome in ST-elevationmyocardial infarction treated with mechanical revasculariza-tionrdquo International Journal of Cardiology vol 158 no 1 pp 103ndash104 2012

[12] I Lymvaios I Mourouzis D V Cokkinos M A DimopoulosS T Toumanidis and C Pantos ldquoThyroid hormone and recov-ery of cardiac function in patients with acutemyocardial infarc-tion a strong associationrdquo European Journal of Endocrinologyvol 165 no 1 pp 107ndash114 2011

[13] C Pantos I Mourouzis T Saranteas et al ldquoAcute T3 treatmentprotects the heart against ischemia-reperfusion injury via TR1205721receptorrdquoMolecular and Cellular Biochemistry vol 353 no 1-2pp 235ndash241 2011

[14] C Pantos I Mourouzis T Saranteas et al ldquoThyroid hormoneimproves postischaemic recovery of function while limitingapoptosis a new therapeutic approach to support hemodynam-ics in the setting of ischaemia-reperfusionrdquo Basic Research inCardiology vol 104 no 1 pp 69ndash77 2009

[15] K K Henderson S Danzi J T Paul G Leya I Klein andA M Samarel ldquoPhysiological replacement of T3 improvesleft ventricular function in an animal model of myocardialinfarction-induced congestive heart failurerdquo Circulation vol 2no 3 pp 243ndash252 2009

[16] I Mourouzis P Mantzouratou G Galanopoulos et al ldquoDose-dependent effects of thyroid hormone on post-ischemic cardiacperformance potential involvement of Akt and ERK signal-ingsrdquoMolecular and Cellular Biochemistry vol 363 no 1-2 pp235ndash243 2012

[17] V Bacci G C Schussler and T B Kaplan ldquoThe relationshipbetween serum triiodothyronine and thyrotropin during sys-temic illnessrdquo Journal of Clinical Endocrinology amp Metabolismvol 54 no 6 pp 1229ndash1235 1982

[18] G A Brent and J M Hershman ldquoThyroxine therapy in patientswith severe nonthyroidal illnesses and low serum thyroxineconcentrationrdquo Journal of Clinical Endocrinology ampMetabolismvol 63 no 1 pp 1ndash8 1986

[19] S-Y Cheng J L Leonard and P J Davis ldquoMolecular aspects ofthyroid hormone actionsrdquo Endocrine Reviews vol 31 no 2 pp139ndash170 2010

[20] C Pantos I Mourouzis and D V Cokkinos ldquoRebuilding thepost-infarcted myocardium by activating ldquophysiologicrdquo hyper-trophic signaling pathways the thyroid hormone paradigmrdquoHeart Failure Reviews vol 15 no 2 pp 143ndash154 2010

[21] C Pantos IMourouzis andDV Cokkinos ldquoThyroid hormoneand cardiac repairregeneration from Prometheus myth torealityrdquoCanadian Journal of Physiology and Pharmacology vol90 no 8 pp 977ndash987 2012

[22] C Pantos I Mourouzis C Xinaris Z Papadopoulou-Daifotiand D Cokkinos ldquoThyroid hormone and ldquocardiac metamor-phosisrdquo potential therapeutic implicationsrdquo Pharmacology ampTherapeutics vol 118 no 2 pp 277ndash294 2008

[23] C Y Ivashchenko G C Pipes I M Lozinskaya et al ldquoHuman-induced pluripotent stem cell-derived cardiomyocytes exhibittemporal changes in phenotyperdquo American Journal of Physiol-ogy vol 305 no 6 pp H913ndashH922 2013

[24] A Liappas I Mourouzis A Zisakis et al ldquoCell type dependentthyroid hormone effects on glioma tumor cell linesrdquo Journal ofThyroid Research vol 2011 Article ID 856050 8 pages 2011

[25] S M van der Heide B J Joosten B S Dragt M E Evertsand P H M Klaren ldquoA physiological role for glucuronidatedthyroid hormones preferential uptake by H9c2(2-1) myotubesrdquoMolecular and Cellular Endocrinology vol 264 no 1-2 pp 109ndash117 2007

[26] HH van der Putten B J Joosten PHKlaren andME EvertsldquoUptake of tri-iodothyronine and thyroxine in myoblasts andmyotubes of the embryonic heart cell line H9c2(2-1)rdquo Journal ofEndocrinology vol 175 no 3 pp 587ndash596 2002

[27] C Pantos C Xinaris I Mourouzis et al ldquoThyroid hormonereceptor 1205721 a switch to cardiac cell ldquometamorphosisrdquordquo Journalof Physiology and Pharmacology vol 59 no 2 pp 253ndash2692008

[28] F Furuya H Shimura S Yamashita T Endo and T KobayashildquoLiganded thyroid hormone receptor-120572 enhances proliferationof pancreatic 120573-cellsrdquo The Journal of Biological Chemistry vol285 no 32 pp 24477ndash24486 2010

[29] Y Hiroi H-H Kim H Ying et al ldquoRapid nongenomic actionsof thyroid hormonerdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 38 pp14104ndash14109 2006

[30] A Kenessey and K Ojamaa ldquoThyroid hormone stimulatesprotein synthesis in the cardiomyocyte by activating the Akt-mTOR and p70S6K pathwaysrdquoThe Journal of Biological Chem-istry vol 281 no 30 pp 20666ndash20672 2006

[31] A Mansen F Yu D Forrest L Larsson and B VennstromldquoTRs have common and isoform-specific functions in regu-lation of the cardiac myosin heavy chain genesrdquo MolecularEndocrinology vol 15 no 12 pp 2106ndash2114 2001

[32] B Gloss S U Trost W F Bluhm et al ldquoCardiac ion channelexpression and contractile function in mice with deletion ofthyroid hormone receptor 120572 or 120573rdquo Endocrinology vol 142 no2 pp 544ndash550 2001

[33] P Tavi M Sjogren P K Lunde et al ldquoImpaired Ca2+ handlingand contraction in cardiomyocytes from mice with a dominantnegative thyroid hormone receptor1205721rdquo Journal ofMolecular andCellular Cardiology vol 38 no 4 pp 655ndash663 2005

[34] M Belakavadi J Saunders NWeisleder P S Raghava and J DFondell ldquoRepression of cardiacPhospholamban gene expressionis mediated by thyroid hormone receptor-1205721 and involvestargeted covalent histone modificationsrdquo Endocrinology vol151 no 6 pp 2946ndash2956 2010

[35] L Wikstrom C Johansson C Salto et al ldquoAbnormal heartrate and body temperature in mice lacking thyroid hormonereceptor 1205721rdquoTheEMBO Journal vol 17 no 2 pp 455ndash461 1998

[36] A Stock and H Sies ldquoThyroid hormone receptors bind to anelement in the connexin43 promoterrdquo Biological Chemistry vol381 no 9-10 pp 973ndash979 2000

[37] T Esaki H Suzuki M Cook et al ldquoCardiac glucose utilizationin mice with mutated 120572- and 120573-thyroid hormone receptorsrdquoAmerican Journal of Physiology vol 287 no 6 pp E1149ndashE11532004

[38] C Pantos I Mourouzis M Delbruyere et al ldquoEffects ofdronedarone and amiodarone on plasma thyroid hormones andon the basal and postischemic performance of the isolated ratheartrdquo European Journal of Pharmacology vol 444 no 3 pp191ndash196 2002

[39] A Makino H Wang B T Scott J X-J Yuan and W H Dill-mann ldquoThyroid hormone receptor-120572 and vascular functionrdquo


American Journal of Physiology vol 302 no 9 ppC1346ndashC13522012

[40] C Sylven E Jansson P Sotonyi F Waagstein T Barkhem andM Bronnegard ldquoCardiac nuclear hormone receptor mrNA inheart failure in manrdquo Life Sciences vol 59 no 22 pp 1917ndash19221996

[41] D D Belke B Gloss E A Swanson and W H Dill-mann ldquoAdeno-associated virus-mediated expression of thyroidhormone receptor isoforms-1205721 and -1205731 improves contractilefunction in pressure overload-induced cardiac hypertrophyrdquoEndocrinology vol 148 no 6 pp 2870ndash2877 2007

[42] K Kinugawa K Yonekura R C Ribeiro et al ldquoRegulationof thyroid hormone receptor isoforms in physiological andpathological cardiac hypertrophyrdquo Circulation Research vol 89no 7 pp 591ndash598 2001

[43] K Kinugawa M Y Jeong M R Bristow and C S LongldquoThyroid hormone induces cardiac myocyte hypertrophy ina thyroid hormone receptor 1205721-specific manner that requiresTAK1 and p38 mitogen-activated protein kinaserdquo MolecularEndocrinology vol 19 no 6 pp 1618ndash1628 2005

[44] G drsquoAmati C R di Gioia D Mentuccia et al ldquoIncreasedexpression of thyroid hormone receptor isoforms in end-stagehuman congestive heart failurerdquo Journal of Clinical Endocrinol-ogy amp Metabolism vol 86 no 5 pp 2080ndash2084 2001

[45] P A Modesti M Marchetta T Gamberi et al ldquoReducedexpression of thyroid hormone receptors and beta-adrenergicreceptors in human failing cardiomyocytesrdquo Biochemical Phar-macology vol 75 no 4 pp 900ndash906 2008

[46] C Pantos I Mourouzis C Xinaris et al ldquoTime-dependentchanges in the expression of thyroid hormone receptor 1205721in the myocardium after acute myocardial infarction possi-ble implications in cardiac remodellingrdquo European Journal ofEndocrinology vol 156 no 4 pp 415ndash424 2007

[47] C Pantos I Mourouzis T Saranteas et al ldquoThyroid hormonereceptors 1205721 and 1205731 are downregulated in the post-infarcted ratheart consequences on the response to ischaemia-reperfusionrdquoBasic Research in Cardiology vol 100 no 5 pp 422ndash432 2005

[48] C Pantos I Mourouzis G Galanopoulos et al ldquoThyroidhormone receptor 1205721 downregulation in postischemic heartfailure progression the potential role of tissue hypothyroidismrdquoHormone and Metabolic Research vol 42 no 10 pp 718ndash7242010

[49] C Pantos C Xinaris I Mourouzis A D Kokkinos and D VCokkinos ldquoTNF-120572 administration in neonatal cardiomyocytesis associated with differential expression of thyroid hormonereceptors a response prevented by T3rdquoHormone andMetabolicResearch vol 40 no 10 pp 731ndash734 2008

[50] H C van Beeren W M Jong E Kaptein T J Visser OBakker and W M Wiersinga ldquoDronerarone acts as a selectiveinhibitor of 3531015840-triiodothyronine binding to thyroid hormonereceptor-1205721 in vitro and in vivo evidencerdquo Endocrinology vol144 no 2 pp 552ndash558 2003

[51] I Mourouzis E Kostakou G Galanopoulos P Mantzouratouand C Pantos ldquoInhibition of thyroid hormone receptor 1205721impairs post-ischemic cardiac performance after myocardialinfarction in micerdquo Molecular and Cellular Biochemistry vol379 no 1-2 pp 97ndash105 2013

[52] R Bassi R HeadsM SMarber and J E Clark ldquoTargeting p38-MAPK in the ischaemic heart kill or curerdquo Current Opinion inPharmacology vol 8 no 2 pp 141ndash146 2008

[53] F B Engel M Schebesta M T Duong et al ldquop38 MAPkinase inhibition enables proliferation of adult mammalian

cardiomyocytesrdquoGenes ampDevelopment vol 19 no 10 pp 1175ndash1187 2005

[54] C Jopling G Sune C Morera and J C I Belmonte ldquop38120572MAPK regulates myocardial regeneration in zebrafishrdquo CellCycle vol 11 no 6 pp 1195ndash1201 2012

[55] S Adamopoulos AGouziouta PMantzouratou et al ldquoThyroidhormone signalling is altered in response to physical trainingin patients with end-stage heart failure and mechanical assistdevices potential physiological consequencesrdquo Interactive Car-diovascular and Thoracic Surgery vol 17 no 4 pp 664ndash6682013

[56] L R Vose G Vinukonda S Jo et al ldquoTreatment with thyroxinerestores myelination and clinical recovery after intraventricularhemorrhagerdquo The Journal of Neuroscience vol 33 no 44 pp17232ndash17246 2013

[57] C I Pantos V A Malliopoulou I S Mourouzis et al ldquoLong-term thyroxine administration protects the heart in a patternsimilar to ischemic preconditioningrdquoThyroid vol 12 no 4 pp325ndash329 2002

[58] F Forini V Lionetti H Ardehali et al ldquoEarly long-term L-T3 replacement rescues mitochondria and prevents ischemiccardiac remodeling in ratsrdquo Journal of Cellular and MolecularMedicine vol 15 no 3 pp 514ndash524 2011

[59] Y-F Chen S Kobayashi J Chen et al ldquoShort term triiodo-l-thyronine treatment inhibits cardiac myocyte apoptosis inborder area after myocardial infarction in ratsrdquo Journal ofMolecular and Cellular Cardiology vol 44 no 1 pp 180ndash1872008

[60] J A Kuzman A M Gerdes S Kobayashi and Q Liang ldquoThy-roid hormone activates Akt and prevents serum starvation-induced cell death in neonatal rat cardiomyocytesrdquo Journal ofMolecular and Cellular Cardiology vol 39 no 5 pp 841ndash8442005

[61] I Mourouzis I Giagourta G Galanopoulos et al ldquoThyroidhormone improves the mechanical performance of the post-infarcted diabetic myocardium a response associated with up-regulation of AktmTOR and AMPK activationrdquo Metabolismvol 62 no 10 pp 1387ndash1393 2013

[62] C Kalofoutis I Mourouzis G Galanopoulos et al ldquoThyroidhormone can favorably remodel the diabetic myocardium afteracute myocardial infarctionrdquo Molecular and Cellular Biochem-istry vol 345 no 1-2 pp 161ndash169 2010

[63] V Rybin and S F Steinberg ldquoThyroid hormone repressesprotein kinase C isoform expression and activity in rat cardiacmyocytesrdquo Circulation Research vol 79 no 3 pp 388ndash3981996

[64] C Pantos V Malliopoulou D D Varonos and D V CokkinosldquoThyroid hormone and phenotypes of cardioprotectionrdquo BasicResearch in Cardiology vol 99 no 2 pp 101ndash120 2004

[65] C Pantos V Malliopoulou I Mourouzis et al ldquoThyroxinepretreatment increases basal myocardial heat-shock protein 27expression and accelerates translocation and phosphorylationof this protein upon ischaemiardquo European Journal of Pharma-cology vol 478 no 1 pp 53ndash60 2003

[66] C Pantos V Malliopoulou I Paizis et al ldquoThyroid hormoneand cardioprotection study of p38 MAPK and JNKs duringischaemia and at reperfusion in isolated rat heartrdquo Molecularand Cellular Biochemistry vol 242 no 1-2 pp 173ndash180 2003

[67] G G Babu J M Walker D M Yellon and D J HausenloyldquoPeri-procedural myocardial injury during percutaneous coro-nary intervention an important target for cardioprotectionrdquoEuropean Heart Journal vol 32 no 1 pp 23ndash31 2011


[68] T Springeling S W Kirschbaum A Rossi et al ldquoLate cardiacremodeling after primary percutaneous coronary intervention-five-year cardiac magnetic resonance imaging follow-uprdquo Cir-culation Journal vol 77 no 1 pp 81ndash88 2012

[69] A M Ranasinghe D W Quinn D Pagano et al ldquoGlucose-insulin-potassium and tri-iodothyronine individually improvehemodynamic performance and are associated with reducedtroponin I release after on-pump coronary artery bypass graft-ingrdquo Circulation vol 114 no 1 pp I245ndashI250 2006

[70] M Sirlak L YaziciogluM B Inan et al ldquoOral thyroid hormonepretreatment in left ventricular dysfunctionrdquo European Journalof Cardio-Thoracic Surgery vol 26 no 4 pp 720ndash725 2004

[71] AM Ranasinghe andR S Bonser ldquoEndocrine changes in braindeath and transplantationrdquo Best Practice and Research vol 25no 5 pp 799ndash812 2011

[72] V Jeevanandam ldquoTriiodothyronine spectrum of use in hearttransplantationrdquoThyroid vol 7 no 1 pp 139ndash145 1997

[73] G V Letsou S Reverdin and O H Frazier ldquoThyrotoxicosis-facilitated bridge to recovery with a continuous-flow left ven-tricular assist devicerdquo European Journal of Cardio-ThoracicSurgery vol 44 no 3 pp 573ndash574 2013

[74] C Grijota-Martınez E Samarut T S Scanlan B Morte andJ Bernal ldquoIn vivo activity of the thyroid hormone receptor 120573-and120572-selective agonistsGC-24 andCO23 on rat liver heart andbrainrdquo Endocrinology vol 152 no 3 pp 1136ndash1142 2011

[75] C A Ocasio and T S Scanlan ldquoDesign and characterizationof a thyroid hormone receptor 120572 (TR120572)-specific agonistrdquo ACSChemical Biology vol 1 no 9 pp 585ndash593 2006

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Terrestrial adult

Metamorph

Aquatic adult

Paedomorph

Aquatic larva

Thyroid hormone

Genesenvironment

(+) (minus)

Figure 1 Critical levels of thyroid hormone (TH) induce metamorphosis in salamanders Low TH can adapt salamander to low oxygenaquatic environment by inducing growth with embryonic characteristics Addition of TH allows adaptation to terrestrial life and completesmetamorphosis Analogies seem to exist in mammals with TH to determine the phenotypic characteristics of the myocardium (pathologicalversus physiological growth) after ischemic events Evolutionary conserved mechanisms of adaptation may be the basis for cardiac repair(Permission by Johnson and Voss [4])

embryonic stagesThis response is likely to be part of an adap-tive response of the living organism to environmental stressThus exposure of air breathing perch to water-born keroseneresulted in low TH and unfavorable metabolic changes whilethe administration of TH reversed this response [5] Alongthis line cold stunning in sea turtles resulted in undetectablethyroid hormone levels and recovery induced by rewarmingwas associated with restoration of TH levels [6] Similarlyin humans TH levels decline after various stresses includingischemia infection and organ failure but the physiologicalrelevance of this response in regard to post-stress adaptationremains largely unknown [7 8]

3 TH Is Critical for the Recovery afterMyocardial Injury

Adecline in T3 levels occurswithin 48 hours(h) aftermyocar-dial infarction (AMI) or 6ndash24 h after cardiac surgery [9 10]Low T3 syndrome is present in nearly 20 of patients withAMI despite primary percutaneous coronary intervention(PCI) Low fT3 levels are associated with lower survivalrate particularly in patients with age less than 75 years [11]indicating that TH may have a role in adapting the heart tomyocardial injury In fact a link of TH to cardiac recoveryafter myocardial infarction has been recently established inhumans and in experimental studies

In a series of patients with AMI and primary PCI leftventricular ejection fraction (LVEF) 48 hours after theindex event was strongly correlated with T3 and not T4 levelsin plasma Furthermore at 6 months recovery of cardiacfunction was correlated with T3 plasma levels and T3 wasshown to be an independent determinant of LVEF recovery[12]

In accordance with this clinical evidence acute T3(and not T4) administration after ischemiareperfusion in

isolated rat hearts resulted in significant improvement ofpostischemic recovery of function [13 14] Furthermorein an experimental model of coronary ligation in micecardiac function was significantly decreased and this wasassociated with a marked decline in T3 levels in plasma T3replacement therapy significantly improved the recovery ofcardiac function [15 16]

On the basis of these data it appears that the active T3 andnot T4 is critical for the response to stress In fact T4 therapyin patients with euthyroid syndrome due to severe illness wasnot shown to be beneficial [17 18]

4 TR1205721 Receptor and Its Physiologic Actions

T3 the active form of TH exerts many of its actions throughits receptors (TRs) TR1205721 TR1205722 TR1205731 and TR1205732 TRswith the exception of TR1205732 are expressed in all tissues andthe pattern of expression varies in different types of tissues[19] TR1205721 is predominantly expressed in the myocardiumand regulates important genes related to cell differentiationand growth contractile function pacemaker activity andconduction [20ndash22]

The importance of TH in organ maturation duringdevelopment and its implication in cell differentiation haslong been recognizedThis unique action seems to be of phys-iological relevance in stem cell biology and cancer [23 24] T3can promote differentiation of human pluripotent stem cellderived cardiomyocytes (hips-CM) [23] and glioma tumorcell lines [24] The implication of TR1205721 in cell differentiationis shown in embryonic myoblast cultures (H9c2) whichis considered a suitable model to study cell differentiationMaturation of H9c2 is TH dependent process [25 26] TR1205721expression is increased in parallel with the intracellularT3 at the stage of cell differentiation and pharmacologicalinactivation of TR1205721 significantly delays cardiac myoblast















140

120

100

80

60

40

20

0


lowastlowast

120572-MHC

AB

CD

120573-MHC



in nucleus)


in nucleus)


in nucleus)

(A)

(B)

(C)

(D)

PE minus T3

PE minus T3 + PD

PE + T3











Cardiac injury





TR1205721

darrT3

uarrTR1205721

darrT3 T3uarrT3









References






















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























140

120

100

80

60

40

20

0


lowastlowast

120572-MHC

AB

CD

120573-MHC



in nucleus)


in nucleus)


in nucleus)

(A)

(B)

(C)

(D)

PE minus T3

PE minus T3 + PD

PE + T3











Cardiac injury





TR1205721

darrT3

uarrTR1205721

darrT3 T3uarrT3









References






















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Cardiac injury





TR1205721

darrT3

uarrTR1205721

darrT3 T3uarrT3









References






















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Review Article The Emerging Role of TR 1 in Cardiac Repair ...

Documents

Transcript of Review Article The Emerging Role of TR 1 in Cardiac Repair ...