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Endocrinology Vol. 147, No. 4 1598-1601
Copyright © 2006 by The Endocrine Society

Thyroid Hormones and 3,5-Diiodothyropropionic Acid: New Keys for New Locks

Paul M. Yen

Associate Professor of Medicine Johns Hopkins University School of Medicine Johns Hopkins Bayview Medical Center Baltimore, Maryland 21224

Address all correspondence and requests for reprints to: Paul M. Yen, M.D., Associate Professor of Medicine, Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue, Room B114, Baltimore, Maryland 21224. E-mail: pyen3{at}jhmi.edu


   Introduction
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 Introduction
Note Added in Proof
 References
 
Thyroid hormones (THs; T4 and the more potent T3) play important roles in the differentiation, growth, and metabolism of virtually every cell in the body (1, 2). In the 1960s, THs were shown to be involved in the transcriptional regulation of target genes as TH treatment of hypothyroid rats caused a rapid increase in RNA synthesis before new protein formation and mitochondrial oxidation (3). Other early studies also showed that radiolabeled TH bound to specific nuclear binding sites in T3-sensitive tissues and thus provided the first evidence for TH receptors (TRs) (4, 5). In the mid 1980s, the Evans and Vennstrom laboratories (6, 7) first isolated and cloned the nuclear TRs. Sequence comparison showed that TRs had homology with the chick viral oncogene product, v-erbA, and belonged to a large superfamily of nuclear hormone receptors that included the steroid, retinoic, and vitamin D receptors as well as orphan receptors for which ligands have not been identified.

There are two major nuclear TR isoforms (TR{alpha} and TRß) that are encoded on separate genes (1, 2). TRs have a carboxy-terminal ligand-binding domain and a central DNA-binding domain that enables them to bind to TH response elements (TREs) in the promoters of target genes and regulate their transcription. In positively regulated target genes, unliganded TRs interact with corepressors, such as nuclear receptor corepressor (NCoR) or silencing mediator for retinoic and thyroid hormone receptors (SMRT), and repress basal transcription by recruiting histone deacetylases and changing the local chromatin structure near the TRE (1, 2). In the presence of T3, corepressor complexes are released from TRs, and liganded TRs associate with coactivator complexes containing the p160 steroid receptor coactivators and histone acetyltransferases such as p/CAF, leading to increased local histone acetylation. TRs also associate with another complex containing vitamin D receptor-interacting protein/ TR-associated proteins (DRIP/TRAPs), some of which are homologous with yeast Mediator proteins and, in turn, help recruit RNA polymerase II and initiate transcription (1, 2). Recent chromatin immunoprecipitation assays have suggested that liganded nuclear hormone receptors, including TRs, recruit coactivators to TREs in a temporal, and perhaps cyclical, pattern (8, 9, 10). Additionally, nuclear TRs also can negatively regulate the transcription of some target genes (e.g. TSH {alpha}- and ß-subunits), although the details of the mechanism(s) are not well understood. The foregoing findings all have led to a classical model of TH action in which nuclear TRs act as ligand-regulatable transcription factors (Fig. 1AGo).


Figure 1
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  		FIG. 1. Classical and nongenomic pathways of TH action. A, T3 is converted from T4 by deiodinase or transported directly into the cell whereupon it binds to nuclear TRs. In positively regulated target genes, corepressors are subsequently released and coactivators recruited, resulting in histone acetylation and RNA polymerase II-mediated transcription. For details see Refs.1 and 2 . B, T4 and T3 binds to integrin {alpha}Vß3 and activates the MAPK pathway. It is possible that nuclear hormone receptors are serine phosphorylated and with down-stream transcriptional regulation result in angiogenesis. Other TH-regulated pathways have been depicted but little is known about their mechanisms. For details see Refs.2 , 11 , and 18 . PLC, Phospholipase C; PKC, protein kinase C; ER{alpha}, estrogen receptor {alpha}; STAT1{alpha}, signal transducer and activator of transcription 1{alpha}.

 
Although many of the effects of TH are mediated by nuclear TRs, there is increasing evidence for nongenomic effects by TH (2, 11). Despite continuous shuttling of a small amount of TRs between the cytoplasm and nucleus (12), the latter events are most likely mediated by cellular binding proteins other than TRs. Evidence supporting this notion comes from the rapid onset of action of some TH effects (typically seconds to minutes and thus precluding transcription and protein synthesis), utilization of membrane-signaling pathways such as kinases or calmodulin, lack of dependence on the presence of nuclear TRs, and structure-function relationships of TH analogs that are different than those observed for nuclear TRs (13).

Over the years, several nonnuclear sites for TH binding have been identified in various cell systems, although their functional significances are not well understood. Some of these include: plasma membrane associated T3 transporters, calcium ATPase, adenylate cyclase, and glucose transporters (1, 2); an endoplasmic reticulum-associated protein, prolyl hydroxylase; and monomeric pyruvate kinase (14, 15). Additionally, it has long been appreciated that TH has profound effects on mitochondrial activity and cellular energy state (16). Recently, a 43-kDa protein has been described in mitochondria, which also could bind to TREs that could be recognized by antibodies against the TR{alpha} ligand-binding domain (17).

Recently, Davis and colleagues (18) identified integrin {alpha}Vß3 as a plasma membrane TH-binding site. Previous studies showed that T4, but not T3, promoted actin polymerization and induced integrin interaction with laminin in neural cells (19). Additionally, other studies showed that both T4 and T3 activated MAPK activity and led, among other events, to phosphorylation of TRß (11). Using a chick chorioallantoic membrane system, Davis et al. showed that both T4 and T3 stimulated angiogenesis. Furthermore, these effects could be reproduced when T4 was linked covalently to agarose and thus could only interact with the plasma membrane. Because integrin {alpha}Vß3 has been implicated in angiogenesis previously, TH binding to this integrin was examined (11). Purified radiolabeled T4 and T3 bound to integrin {alpha}Vß3 reversibly and with high affinity. A RGD (Arg-Gly-Asp) peptide that contains the recognition site critical for integrin interaction with extracellular matrix proteins such as laminin blocked T4 binding to the integrin. Tetraiodothyroacetic acid and antibodies against laminin also had similar effects on T4 binding. Moreover, small interfering RNAs against the integrin {alpha}V or ß3 subunits blocked MAPK activation by TH in CV-1 cells. Taken together, these data provide strong evidence that TH activates the MAPK cascade and stimulates angiogenesis via TH binding to integrin {alpha}Vß3 (Fig. 1BGo).

Our increased understanding of the classical and nongenomic pathways of TH action has generated strong interest in developing drugs that can take advantage of salubrious TH effects on important physiological processes such as cholesterol homeostasis, energy metabolism, and cardiac performance. Thus far, several tissue-specific and TR isoform-specific compounds have been developed that are geared, in principle, toward potential treatment of conditions such as hypercholesterolemia and obesity (Fig. 2Go). An early example of these compounds was 3,5-dibromo-3-pyridazinone-L-thyronine (L-940901), which bound preferentially to TRs in liver than in heart (20). Although the relative affinity of this compound for TR isoforms has not been reported, the selective action of L-940901 is presumed to be primarily due to tissue-specific uptake of the compound. Of note, mice treated with L-940901 had decreased serum cholesterol levels without cardiotoxicity. In this connection, the recent identification of TH transporters such as the MCT8 and System L transporters should provide potential new targets for designing tissue-selective TH analogs (21, 22). Recently, several other TH analogs have been described that have selective affinity for TR isoforms, in particular, TRß compared with TR{alpha}. Because TRs in the liver are approximately 90% TRß, and in the heart mostly TR{alpha}, these isoform-selective compounds may serve as novel agents to lower serum cholesterol with minimal cardiac toxicity (1, 2). N-[3,5-Dimethyl-4-(4'-hydroxy-3'isopropylphenoxy)-phenyl]-oxamic acid (CGS 23425), 3,5-dimethyl-4(4'-hydroxy-3'-isopropylbenzyl)-phenoxy) acetic acid (GC-1), and 3,5-dichloro-4[(4-hydroxy-3-isoopropylphenoxy)phenyl] acetic acid (KB-141) all have been reported to lower total serum cholesterol and low-density lipoprotein-cholesterol (23, 24, 25) (Fig. 2Go). CGS 23425 has been shown to increase low-density lipoprotein receptor expression in HepG2 cells (23). Additionally, these compounds also can increase serum apoA1 levels; however, total serum high-density lipoprotein (HDL) cholesterol may be unchanged or even decreased. In the latter case, GC-1 decreased serum HDL in treated mice; increased expression of HDL receptor SR-B1; stimulated the activity of cholesterol 7{alpha} hydroxylase; and increased fecal excretion of bile acids (26). Thus, GC-1 can regulate key steps in the reverse cholesterol transport pathway. Finally, KB141 has shown promise in decreasing body weight by stimulating metabolic rate and oxygen consumption (25).


Figure 2
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  		FIG. 2. Structure of T3 and TH analogs. CGS 23425, GC-1, and KB-141 are selective for TRß. T1AM binds to the trace amine receptor TAR1. DITPA binds both nuclear TR isoforms with decreased affinity. Both GC-1 and DITPA bind integrin {alpha}Vß3. [Reprinted in part from Ref.28 with permission from Elsevier.]

 
TH analogs and derivatives also have been shown to bind specifically to proteins other than TRs and shed light on nongenomic functions by these compounds. Recently, Scanlan et al. (27) identified 3-iodothyronamine (T1AM), which is a naturally occurring byproduct of TH, as a potent agonist of the G protein-coupled trace amine receptor, TAR1. This compound had poor affinity for nuclear TRs. Interestingly, T1AM produced a rapid drop in body temperature and heart rate when injected ip in mice. T1AM also decreased cardiac output in an ex vivo working heart model. Thus, some of the physiological actions of T1AM opposed those observed for T3. Accordingly, the authors have proposed that the metabolism of TH may be an important regulator of TH action, as T4-to-T3 conversion by deiodinases determines the amount of ligand for nuclear TRs in the classical pathway, whereas deiodination and decarboxylation of THs to T1AM provides a counterregulation to the transcriptional effects of TH by nuclear TRs.

TH can increase cardiac performance by increasing cardiac contractility and decreasing systemic vascular resistance (28). These beneficial effects by TH have been mitigated by side effects such as tachycardia and metabolic stimulation. However, 3,5-diiodothyropropionic acid (DITPA) is a TH-related compound with low metabolic activity and relatively low affinity for nuclear TRs (Kd, 10–7 M) (28). In animal studies, DITPA was able to increase cardiac contractility and peripheral circulation without significant effects on heart rate. Moreover, DITPA improved hemodynamic parameters in animal models of congestive heart failure after myocardial infarction. Initial studies in patients with heart failure treated with DITPA showed significant improvement in systolic cardiac index and systemic vascular resistance (29). Currently, phase II trials are underway to test DITPA’s efficacy in heart failure as well as hypercholesterolemia (28).

In this current issue, Davis and colleagues (30) have examined the effects of DITPA on angiogenesis and its interaction with the integrin {alpha}Vß3. They showed that both T4 and T3 increased angiogenesis in the chorioallantoic membrane system and an in vitro three-dimensional human microvascular endothelial sprouting assay. Additionally, DITPA, basic fibroblast growth factor, and vascular endothelial cell growth factor produced similar effects in these systems, and angiogenesis could be blocked by an inhibitor of MAPK signaling, PD 98059. An integrin {alpha}Vß3 antagonist, XT199, also blocked the angiogenesis stimulated by DITPA and basic fibroblast growth factor. Taken together with their previous work on THs, these novel findings suggest that DITPA may promote angiogenesis by interacting with membrane-bound integrin {alpha}Vß3 and activating the MAPK cascade. Of note, it previously was reported that DITPA was angiogenic in a postinfarction rat heart model (31); thus, it is possible that some of the beneficial effects of DITPA on cardiac contractility could be mediated by this nongenomic mechanism. Additionally, it appears that another TH analog, GC-1, can interact with integrin {alpha}Vß3 (32), and this raises the possibility that some of the effects attributed to GC-1, perhaps even some of its metabolic effects, may be mediated by nongenomic mechanisms. In the future, it will be important to clarify the precise roles of TH in the classical and nongenomic pathways. Microarray and proteomic approaches will greatly facilitate this enterprise. At the same time, as our knowledge of both types of pathways increases, it should be possible to design drugs that take advantage of the down-stream effects of one pathway without the side effects of the other(s). Hopefully, further studies on the basic mechanisms and clinical application of drugs like DITPA will be harbingers of more good things to come by providing new keys to open new locks.


   Note Added in Proof
Top
 Introduction
 Note Added in Proof
References
 
Recently, it has been shown that TRß can interact with the p85 subunit of PI3K and activate the PI3K-Akt/PKB signaling cascade, suggesting that the small subpopulation of cytosolic TRß may be involved in cell signaling (33). Of note, PI3K activation by T3 leads to both direct and indirect effects on the transcription of several genes involved in glucose metabolism (34).


   Footnotes
 
The author has nothing to declare.

Abbreviations: DITPA, 3,5-Diiodothyropropionic acid; HDL, high-density lipoprotein; T1AM, 3-iodothyronamine; TH, thyroid hormone; TR, TH receptor; TRE, TH response element.

Received January 19, 2006.

Accepted for publication February 1, 2006.


   References
Top
 Introduction
 Note Added in Proof
 References
 

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