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(Circulation Research. 2001;89:557.)
© 2001 American Heart Association, Inc.

Editorial

When the Thyroid Speaks, the Heart Listens

Mark A. Sussman

From The Children’s Hospital and Research Foundation, Division of Molecular Cardiovascular Biology, Cincinnati, Ohio.

Correspondence to Mark A. Sussman, The Children’s Hospital and Research Foundation, Division of Molecular Cardiovascular Biology, Room 3033, 3333 Burnet Ave, Cincinnati, OH 45229. E-mail sussman{at}heart.chmcc.org

Key Words: thyroid receptor • hypertrophy • transcription • hormone • heart

Thyroid hormone (TH, triiodothyronine, T₃) signaling is critical for proper heart development and function. Myocyte-specific genes regulated by TH comprise a "who’s who" list of proteins responsible for cardiomyocyte function: myosin heavy chain (MHC), sarcoplasmic reticulum calcium-activated ATPase (SERCA), phospholamban, - and ß-adrenergic receptors, adenyl cyclase, protein kinase C, and a variety of ion channels. With this list of players, it is not surprising that alterations in TH stimulation have significant consequences for cardiac function including heart rate, contractility, and mass. The multiple effects of TH upon function of the cardiovascular system were recently summarized in an excellent review.¹

The importance of regulating TH stimulation during the process of normal cardiac development has been established, particularly with regard to postnatal changes. Maturation of the myocardium depends upon increasing TH signaling after birth, which induces growth and the transcriptional reprogramming that leads to the characteristic gene expression profile of the adult heart. More than a decade has passed since initial reports showed the gene expression profile of the fetal heart (where TH stimulation is relatively low) was recapitulated in the hypertrophic and/or failing myocardium. This seminal observation suggestive of dysfunctional TH signaling spawned numerous investigations to examine the potential benefit of manipulating TH signaling to mitigate heart failure.² However, using TH in a therapeutic context to combat reactivation of fetal gene expression in the failing heart may be hampered by altered expression of the appropriate thyroid receptors (TRs) needed to transduce TH signals.

Two TR isoforms, designated TR1 and TRß1, which can bind TH with similar affinity, are present within the heart. A third isoform, TR2, is a splice variant of TR1 that does not bind TH and can act as a dominant-negative protein for TR signaling. Significance of a fourth isoform, TRß2, remains unresolved since low levels of expression can only be detected by reverse transcription–polymerase chain reaction. Transgenic mouse models have shown that cardiac-restricted overexpression of mutant TRß1, which acts as a potent dominant-negative inhibitor of TR signaling, results in a hypothyroid heart phenotype.^3,4 Thus, diminished TR signaling can precipitate changes in gene expression consistent with heart failure, even under euthyroid conditions. Earlier this year, Kinugawa and colleagues⁵ offered support for this principle at the mRNA level by showing that failing human hearts possessed higher levels of TR2 and diminished levels of TR1, while TRß1 remained unchanged. These results remain controversial, as other investigations of TR mRNA expression in failing human hearts found elevation of TRß1 with lowered levels of TR1 and 2⁶ or increased expression of TR1, 2, and ß1.⁷ Adding to the confusion, TRß1 and ß2 mRNA upregulation was observed in dogs suffering from heart failure.⁸ The puzzle of TR expression and function continues to be pieced together in this issue of Circulation Research, with Kinugawa et al⁹ offering a new twist to the idea that altered TR expression correlates with transcription profiles of TH-responsive target genes.

Transcriptional reprogramming in hypertrophic remodeling is accepted dogma, and the new study by Kinugawa et al⁹ reinforces the concept that TR expression levels are influenced by various hypertrophic stimuli, either in vitro with neonatal rat cardiomyocytes or in vivo with adult rats. The new twist is to link TR expression to the kind of hypertrophic stimulation: namely, physiological versus pathological. Physiological hypertrophy induced by TH treatment in vitro or voluntary exercise in vivo was characterized by elevation of -MHC and SERCA and repression of ß-MHC expression. Opposite effects for expression levels of these genes resulting from phenylephrine treatment in vitro or pressure overload after aortic constriction in vivo were deemed pathological hypertrophy. The two different types of hypertrophy evoked distinct characteristic changes in TR expression profiles: physiological stimulation increased TRß1 while TR1 and 2 were unaffected, whereas pathological stimulation decreased all three TR isoforms (Figure). These consistent correlative findings between in vitro and in vivo experiments suggest that TR isoform expression modulates TH-responsive gene expression. In an attempt to establish this relationship directly, cultured cardiomyocytes were cotransfected with plasmids encoding specific isoforms of human TR protein together with other plasmids carrying a TH-responsive promoter (-MHC, ß-MHC, or SERCA) linked to a reporter gene. Comparison of reporter construct activity with each overexpressed TR isoform revealed that different TR isoforms exhibit distinct transcriptional activity profiles. TR1 activated the -MHC promoter, TRß1 repressed the ß-MHC promoter, and TR2 had no effect on any of the three reporter constructs. This result supports the concept of TR-dependent regulation of TH-responsive genes and provides evidence that TH-responsive promoters are differentially regulated by the various TR isoforms. Overexpression of either TR1 or ß1 counteracted the phenotypic effects of phenylephrine treatment upon -MHC promoter activity or ß-MHC and SERCA promoter activity, respectively. The conclusion that TH-responsive promoters are selectively regulated by different TR isoforms was reinforced by the final set of experiments in the study, which used treatment of cultured cardiomyocytes with GC-1 (a TRß1-selective agonist). Preferential activation of TRß1 by GC-1 repressed ß-MHC reporter gene expression, analogous to results obtained by overexpression of TRß1.

View larger version (24K): [in this window] [in a new window]   Signaling effects of hypertrophic stimulation (physiological or pathological) compared with human heart failure. Expression levels of mRNA for thyroid hormone (TH) receptor (TR, middle row) or TH-responsive target genes (bottom row) show characteristic increases (upward arrow), decreases (downward arrow), or no change (dash). Human heart results as reported by Kinugawa et al.5 PE indicates phenylephrine.

Involvement of TR as modulators of TH-responsive signaling introduces another mechanism to account for transcriptional reprogramming associated with cardiac remodeling in the hypertrophied or failing heart. If altered TR expression is contributory to reactivation of the fetal transcriptional profile, then Kinugawa et al⁹ provide another explanation for the beneficial effect of TH treatment for heart failure. Clinical investigations have established that patients suffering from heart failure also possess low serum TH levels. Patients respond favorably to short-term TH supplementation with increased cardiac output and exercise performance.^10,11 Left ventricular hypertrophy induced by pressure overload in rats also responds favorably to TH treatment with improved cardiac function and increased expression of -MHC and SERCA proteins.¹² Since TRß1 expression was increased by TH in cultured cardiomyocytes in the present study by Kinugawa et al,⁹ TH administration may act to normalize depressed TR expression and favor the adult transcriptional phenotype under cardiomyopathic conditions.

As is often the case with novel research, this report from Kinugawa et al⁹ raises more questions than it answers. The relationship between TR and heart failure requires additional studies to resolve discrepant findings that have already appeared in the literature. First, it is important to understand the circumstances resulting in altered TR expression during cardiac remodeling and failure. Published results are inconsistent,^5–8 perhaps owing to sample population differences or methodological techniques, but a consensus view of TR isoform expression in human heart disease would be invaluable. Further studies in animal models and cultured cells where conditions can be rigorously controlled will be helpful, especially in assessing the impact of TH manipulation upon TR expression. However, possible species-specific differences in expression of cardiac TR isoforms need further clarification to help extrapolate from experimental paradigms to human hearts.¹³ Also, posttranslational regulation of TR signaling by phosphorylation in the heart remains unexplored but has been observed in other systems.¹⁴ Regarding the functional properties of TR isoforms, the dominant-negative impact of TR2 was curiously absent from transfection experiments in the Kinugawa et al⁹ study, with overexpression of TR2 having no discernible effect upon gene transcription induced by TH treatment of cultured cardiomyocytes.

Kinugawa et al⁹ point out that the question of whether both TR1 and ß1 are required for appropriate TH stimulation in the heart remains unanswered, although their findings suggest that the answer is probably yes. Their study shows that TH induces expression of TRß1 mRNA alone with concomitant increases in -MHC and SERCA mRNA, while ß-MHC mRNA expression decreases. Yet TRß1 overexpression has negligible effects upon induction of either -MHC or SERCA mRNA levels in transfection experiments. Multiple studies have linked TR1 with expression of -MHC, so it would seem that accumulation of TRß1 cannot substitute for TR1-mediated signaling. Similarly, overexpression of TR1 fails to overcome phenylephrine-induced expression of ß-MHC mRNA that is repressed by accumulation of TRß1.

Of course, the ultimate goal of understanding myocardial TR signaling is to apply this information to the treatment of heart disease. Overexpression of TH-binding TR can antagonize reversion to a fetal gene expression profile, thereby preventing the deleterious changes in protein levels for -MHC and SERCA that contribute to impairment of cardiac performance. Transgenic mice could be designed to test the beneficial effect of TR expression in a model of pressure overload or dilated cardiomyopathy. Recent efforts to genetically engineer heightened cardiac-specific TH stimulation in transgenic mice (by overexpression of the enzyme that catalyzes intracellular TH conversion) failed to elevate intracellular TH levels or affect expression of TH-responsive proteins,¹⁵ so an alternative approach using TRs may prove more fruitful. Bioavailability of TH in the myocardium may be a limiting factor, and future studies will need to factor this possibility into the design of experimental approaches for enhancing TH signaling in the myocardium. Understanding the interdependence between TR expression and myocardial TH signaling will be critical for understanding the molecular basis for heart failure and the design of interventional treatment approaches. Future research will ensure that, when the thyroid speaks, the heart will listen and respond favorably.

Acknowledgments

The author would like to thank Drs Jeff and Jeff (Robbins and Molkentin) for their critical reading of the manuscript.

Footnotes

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

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