Cardiac actions of thyroid hormone metabolites Grazia Rutiglianoa,b, Riccardo Zucchic*
a Scuola Superiore Sant’Anna, Piazza Martiri della Libertà 33, 56127 Pisa, Italy
b National Research Council (CNR) - Institute of Clinical Physiology (IFC), Via Giuseppe Moruzzi 1, 56124 Pisa, Italy
c Department of Pathology, University of Pisa, Via Roma 55, 56126 Pisa, Italy
*Corresponding author: Riccardo Zucchi, Laboratory of Biochemistry, Department of Pathology, University of Pisa, Via Roma 55, 56126 Pisa, Italy e-mail: riccardo.zucchi@med.unipi.it
Abstract
Thyroid hormones (THs) have a major role in regulating cardiac function. Their classical mechanism of action is genomic. Recent findings have broadened our knowledge about the (patho)physiology of cardiac regulation by THs, to include non-genomic actions of THs and their metabolites (THM). This review provides an overview of classical and non-classical cardiac effects controlled by: i) iodothyronines (thyroxine, T4; 3,5,3’-triiodothyronine ,T3; 3, 5-diiodothyronine, T2); ii) thyronamines (thyronamine, T0AM;
3-iodothyronamine , T1AM); and iii) iodothyroacetic acids (3, 5, 3’, 5’-tetraiodothyroacetic acid, tetrac; 3, 5, 3’-triiodothyroacetic acid, triac; 3-iodothyroacetic acid, TA1). Whereas iodothyronines enhance both diastolic and systolic function and heart rate, thyronamines were observed to have negative inotropic and chronotropic effects and might function as a brake with respect to THs, although their physiological role is unclear. Moreover, thyronamines showed a cardioprotective effect at physiological concentrations. The cardiac effects of iodothyroacetic acids seem to be limited and need to be elucidated.
Keywords: thyroid hormones; 3, 5-diiodothyronine; 3-iodothyronamine; thyroacetic acids; non-genomic effects; cardioprotection.
Abbreviations
ADP, adenosine diphosphate; Akt, Ak strain transforming; ATP, adenosine triphosphate; CaM, calmodulin; D2, type II deiodinase; D3, type III deiodinase; Ina, sodium current; MAPK, Mitogen-activated protein kinase; MHC, myosin heavy chain; ROS, reactive oxygen species; rT3, 3,3’,5’-triiodothyronine SERCA, sarcoplasmic reticulum Ca2+-ATPase; T0AM, thyronamine; T1AM, 3-iodothyronamine; T2, 3,
5-diiodothyronine; T3, 3,5,3’-triiodothyronine; T4, thyroxine; TA1, 3-iodothyroacetic acid; TAAR1, trace amine associated receptor-1; Tetrac, 3, 5, 3’, 5’-tetraiodothyroacetic acid; THM, thyroid hormone metabolites; THs, thyroid hormones; TREs, thyroid hormone response elements; Triac, 3, 5, 3’-triiodothyroacetic acid; TRs, thyroid hormone receptors.
1. Introduction
Thyroid hormones (hereby, THs) have a well-established role in regulating heart function. Classically, it was believed that THs act through specific nuclear receptors, TRs, which interact with TH response elements (TREs) in the regulatory regions of several genes to modulate gene transcription (McKenna and O'Malley, 2002). It is now well known that some of TH actions appear within minutes, and cannot be explained with a genomic mechanism. Adding to this, TH metabolites (hereby, THM), mainly 3, 5-diiodothyronine (3, 5-T2) and 3-iodothyronamine (T1AM) have emerged as independent chemical messengers with their own peculiar effects (Accorroni et al., 2016; Goglia, 2014; Hoefig et al., 2016; Zucchi et al., 2014).
Within the cardiomyocytes, THs are subjected to tissue-specific metabolism, encompassing deiodination and possibly decarboxylation and deamination. As a substrate of deiodinases, thyroxine (T4) can be converted either to 3,5,3’-triiodothyronine (T3) or reverse T3 (3,3’,5’-triiodothyronine , or rT3), whose deiodination yields diiodothyronines, i.e. 3, 5-diiodothyronine (3, 5-T2), 3, 3’-diiodothyronine and 3’, 5’-diiodothyronine. Alternatively, THs can undergo deamination and decarboxylation, producing biologically active molecules, respectively thyroacetic acids and thyronamines. In particular, T1AM was found to induce functional effects via a non-genomic mechanism. T1AM is a substrate of deiodinases, yielding thyronamine (T0AM), and amine oxidases, which eventually produce 3-iodothyroacetic acid (TA1) (Senese et al., 2014; Visser and Peeters, 2000).
In this review we will cover the cardiovascular effects of the THM throughout the TH metabolic pathway. Available data on receptors and transduction pathways will be reviewed, controversial questions will be highlighted, with a focus on the potential clinical implications of recent research advances.
2.1. Cardiac actions of iodothyronines (T4, T3, T2)
THs have long been known to produce a positive inotropic and chronotropic effect, i.e. to increase cardiac contractility and heart rate. This has been classically attributed to modulation of gene expression by T3. The myocardium expresses different forms of TRs, predominantly TRα1, followed by TRβ1 and TRβ2 (Schwartz et al., 1994). TRs show much higher affinity (about 100-fold) for T3 than for T4. While total serum T4 exceeds serum T3 by two orders of magnitude, in rat cardiac tissue T3 and T4 concentrations are comparable, on the order of 1 pmol/g, probably due differences in transmembrane transport and to local T3 production from T4 by type II deiodinase (D2) (Saba et al., 2010; Weltman et al., 2014). So, T3 is thought to play the dominant role in modulating gene expression. Under the control of THs a shift occurs from the α to the β chains of the myosin heavy chain (MHC) (Morkin et al., 1983). THs upregulates the sarcoplasmic reticulum Ca2+-ATPase (SERCA) (Zarain-Herzberg et al., 1994), the 1 adrenergic receptor (Bahouth, 1991), the 2 and 1 subunits of the Na+/K+ ATPase (Huang et al., 1994), and two voltage-gated potassium channel isoforms
(Kv4.2 and Kv4.3) (Shimoni et al., 1997), thereby enhancing both diastolic and systolic function and heart rate (Accorroni et al., 2016).
Cardiac function is also indirectly affected by vascular effects. THs reduce vascular resistance both as a consequence of the increased metabolic rate and through direct effects on signaling pathways regulating vascular smooth muscle tone. In particular, TH reduces the expression of angiotensin type I receptor (ref) and increases NO production (come?) (refs). In turn, peripheral vasodilation activates vasopressor reflexes, inducing tachycardia, and activates the renin-angiotensin-aldosterone system, favoring renal sodium reabsorption and preload expansion (refs).
In different experimental and clinical settings, TH administration modified heart rate and cardiac output within seconds or minutes, and this time course suggested the occurrence of non-genomic actions (reviewed in (Accorroni et al., 2016)). Subsequent investigations confirmed non-genomic modulation of ion transporters and channels, affecting Ca2+, Na+ and K+ currents. NO production may also be stimulated in a non-genomic way. These effects are likely to be mediated by different transduction pathways, possibly involving membrane receptors, like integrin αV3, or cytosolic TRs, that might be coupled to the Akt and/or MAPK signaling systems. With regard to non-genomic responses, a significant role might be played also by T4 (Accorroni et al., 2016).
Another important target of the TH signaling system is represented by the extracellular matrix. Hypothyroidism has long been known to be associated to interstitial fibrosis and increased extracellular water content, leading to a state known as myxedema. The basic molecular event is an increased production of glycosaminoglycans, particularly hyaluronic acid (è vero?). This is usually believed as a response triggered by autoantibody-mediated stimulation of fibroblast TSH and/or IGF-1 receptors (Bartalena et a, JCI, 2014 e altre refs). Fibrosis leads to tissue stiffness, which contributes to impair myocardial relaxation and to increase vascular resistance.
Changes in TH levels are obviously responsible for the cardiac abnormalities observed in hyperthyroidism and hypothyroidism. There is also evidence that local changes in cardiac TH metabolism may play a role in non-endocrine disease. In particular, in several experimental models of heart failure cardiac type III
deiodinase (D3) activity was increased, leading to a local hypothyroid state (Pol et al., 2010). Whether tissue hypothyroidism also occurs in human heart failure is still an open and controversial issue (Gerdes and Iervasi, 2010).
3, 5-diiodo-L-thyronine (3, 5-T2) has gained attention in the search for antiobesity drugs with no
thyromimetic side effects, and because of its illegitimate use in body builder communities. In order to test 3, 5-T2 putative beneficial metabolic effects and cardiac side effects, a murine model of diet-induced obesity was treated with 0.25 or 2.5 µg/g for 14 days and was found to develop significant cardiac
hypertrophy associated with genomic effects overlapping with those of THs (Jonas et al., 2015). On the contrary, studies administering 3, 5-T2 dosages of 0.25 to 0.75 µg/g yielded different results, namely no effect of 3, 5-T2 on heart rate and heart mass, despite an increase in the heart mass:body mass ratio at the highest dose. The latter was most likely due to decreased body mass, as chronic (90 days) treatment with 3, 5-T2 significantly improved metabolic status, reducing body mass gain and retroperitoneal fat mass, and stimulating resting metabolic rate (Goglia, 2015; Padron et al., 2014). Preliminary clinical data are available though limited to only two euthyroid subjects, who after 3-week treatment with 3,5-T2 (300 g/day) presented with increased resting metabolic rate and decrease body weight, and without any change in cardiac parameters (Antonelli et al., 2011).
In summary, specific 3, 5-T2 actions on the heart have not emerged as yet, although its chronic
administration endorses the potential to cause cardiac enlargement. Some questions should be specifically addressed to elucidate the physiological relevance of the described findings. It is unclear whether
endogenous 3, 5-T2 originates from THs via deiodination or whether it also derives from thyroglobulin during TH biosynthesis. In addition, reliable assays able to determine the endogenous 3, 5-T2 concentration are necessary. 3,5-T2 has been detected in serum by different immunological and mass spectrometry-based techniques (reviewed in (Accorroni et al., 2016)), but the results have been quite different, and tissue levels have never been determined. Finally, the binding sites of 3, 5-T2 have not been unambiguously identified. 3, 5-T2 has a low affinity for TRβ, which can account for its thyromimetic effects at high dosages (Mendoza et al., 2013), but direct mitochondrial actions have been claimed (Davis et al., 2016), although no specific receptor has been identified so far.
2.2. Cardiac action of thyronamines
The first report about the biological properties of T0AM dates back to 50 years ago, when it was found to have spasmolytic, anti-histamine, anti-serotonin, and anti-oxytoxic activity in vitro on the smooth muscle, and to increase cardiac contractility with no change in heart rate and arterial blood pressure in the intact animal (Buu-Hoi et al., 1966). After a decade, another group described a positive inotropic and chronotropic effect induced in the dog by T0AM, with onset and peak within 10 min. As such haemodynamic effects were diminished by adrenergic blockade, they concluded that T0AM actions depended on catecholamine release (Cote et al., 1974). More recently, our group showed that in ex vivo working rat heart preparations, T1AM treatment reduced cardiac output, aortic pressure, coronary flow, and heart rate. The inotropic and chronotropic actions were dose-dependent and could be dissociated, with IC50’s of 27µM and 37µM, respectively (Chiellini et al., 2007; Scanlan et al., 2004). T0AM also decreased cardiac output, but it was less potent than T1AM and had only minor effects on heart rate (Chiellini et al., 2007). A negative inotropic effect of T1AM was confirmed in a cardiomyocyte preparation (Ghelardoni et al., 2009). The differences
with the previous reports might be accounted for by the central nervous system excitatory effect produced by T0AM in the in vivo model, which was abolished in our ex vivo denervated model. Notably, in presence of catecholamine depletion and/or adrenergic blockade, a positive inotropic response to T0AM infusion was observed also in the dog model (Cote et al., 1974).
Endogenous T1AM concentrations in rat hearts lie in the nanomolar range (Chiellini et al., 2007; Saba et al., 2010). Since the observed actions occurred at concentrations three orders of magnitude higher than the endogenous levels, it seems implausible that T1AM may modulate heart rate and contractile function under physiological conditions, although the subcellular distribution of T1AM and of its putative receptors is unclear (see below) and therefore its concentration at receptor level remains unknown. However it is possible that endogenous T1AM may have importance in pathophysiological conditions. Particularly, lower concentrations (125 nM to 1.25 µM) of T1AM showed cardioprotective effects in an isolated rat heart model of ischemia-reperfusion injury (30 min of global normothermic ischemia followed by 120 min of retrograde reperfusion), reducing infarct size in the absence of any hemodynamic effect. The dose-response curve was bell-shaped and concentrations greater than 12.5 µM were ineffective (Frascarelli et al., 2011).
The negative inotropic and chronotropic responses to thyronamines were rapid and readily reversible, supporting the involvement of non-genomic effectors. The receptor originally identified as the target of T1AM is trace amine associated receptor-1 (TAAR1) (Scanlan et al., 2004). However, it is unclear whether T1AM produces its cardiac effects through TAAR1, since at least five diverse TAAR subtypes are expressed in the rat heart, with RT-PCR revealing TAAR8a to be the main subtype, (Chiellini et al., 2007) and the
pharmacological characterization of other trace amines showed that the rank of potency did not correspond to the affinity for TAAR1 (Frascarelli et al., 2008). As reviewed elsewhere (Hoefig et al., 2016; Zucchi et al., 2014) additional targets have been recently identified for T1AM, including other TAAR subtypes (particularly TAAR5), α-2A-adrenergic receptor (Regard et al., 2007), and membrane transporters. T1AM might also act on intracellular targets, consistently with the recent report of a 30-fold gradient between intracellular and extracellular compartments in isolated cardiomyocytes (Saba et al., 2010). The specific transporters responsible for translocation across the plasma membrane are still to be identified, but transporters of other monoamines, organic cations, and thyroid hormones do not appear to be involved (Ianculescu et al., 2009). In several human cells lines, T1AM uptake was sodium–independent and pH-dependent (Ianculescu et al., 2009), but experiments performed in H9c2 cardiomyoblasts suggested a high-affinity,
sodium-dependent transport mechanism (Saba et al., 2010). Interestingly, evidence for the presence of intracellular TAAR1 has been obtained in neurons (Bunzow et al., 2001), while other as-yet poorly identified binding sites for T1AM might be present in mitochondria, possibly associated with sub-mitochondrial particles and soluble F1-ATPase (Cumero et al., 2012).
The transduction pathway(s) supporting T1AM haemodynamic actions was investigated with a
pharmacological approach. Inhibitors of protein kinase A, protein kinase C, calcium-CaM-dependent kinase II, phosphatidylinositol-3-kinase, MAP kinase-2, and MAP kinase kinase did not influence the response to T1AM. On the contrary, genistein, a tyrosine kinase inhibitor, accentuated T1AM effects on cardiac output and heart rate, whereas they were suppressed by vanadate, a tyrosine phosphatase inhibitor. Furthermore, in Western blot experiments T1AM was observed to alter the phosphorylation status of tyrosine residues in cytosolic and microsomal proteins (Chiellini et al., 2007). These findings support the hypothesis that the transduction pathway initiated by T1AM may involve the activation of phosphotyrosine phosphatases with subsequent dephosphorylation of tyrosine residues, which is accentuated if baseline tyrosine kinase activity is impaired by genistein (Chiellini et al., 2007). This hypothesis requires further evaluation, since both genistein and vanadate may have additional effects, but, intriguingly, there is evidence that tyrosine kinases and phosphatases might affect the subcellular distribution of channel proteins and/or their association with ancillary proteins (Moral et al., 2001; Ogura et al., 1999), which can in turn modulate ionic homeostasis. Exposure of cultured H9c2 cardiomyocytes to T1AM decreased cellular shortening and prolonged action potential duration (Ghelardoni et al., 2009), which may be accounted for by its effects on depolarization-induced calcium transients and repolarizing ionic currents. As for the former, reduced amplitude and duration the calcium transient could be due to increased diastolic calcium leak from the sarcoplasmatic reticulum (SR), leading to depletion of SR calcium pool. As regards the latter, inhibition of the delayed rectifier potassium current was observed by electrophysiological experiments (Ghelardoni et al., 2009).
The cardioprotective effect of T1AM appears to rely on different signaling pathways. T1AM probably modulated the susceptibility to ischemia-reperfusion injury via mechanisms known to be involved in ischemic preconditioning, such as protein kinase C and ATP-dependent K+ channels (Ertracht et al., 2014; Simkhovich et al., 2013), as its protective effects were reversed by both chelerythrine, a specific PKC inhibitor, and glybenclamide, an inhibitor of the KATP+-channel (Frascarelli et al., 2011).
A key effector of the ischemia/reperfusion injury pathways is mitochondrial permeability transition (Di Lisa and Bernardi, 2015) and it has been speculated that the latter may be eventually antagonized by T1AM. However, at present this hypothesis rests only on circumstantial evidence, namely: 1) the cardioprotective effect of T1AM was not additive to that of cyclosporine A (Frascarelli et al., 2011), a well-known inhibitor of mitochondrial permeability transition; 2) mitochondrial effects of T1AM have been described. In rat liver mitochondria, T1AM was observed to operate a partial block of the electron flow through the respiratory chain thereby affecting the rate of oxygen consumption and reactive oxygen species (ROS) release. Since these effects were abolished in presence of antimycin A, most probably T1AM reduced the activity of Complex III (Venditti et al., 2011). T1AM has also been reported to regulate the steady-state binding of F0F1-ATP synthase to its natural inhibitor protein, IF1 (Watt et al., 2010). At nanomolar concentrations
T1AM displaced IF1 from its binding site in the F1 particle, while at micromolar concentrations T1AM inhibited ATP synthase activity (Cumero et al., 2012). These effects might theoretically affect the rate of ATP consumption and ROS generation during ischemia-reperfusion, which might in turn affect permeability transition and the development of irreversible tissue injury, but it should be acknowledged that no cause to effect relationship has been demonstrated so far.
2.3. Cardiac actions of thyroacetic acids
In the mid 1950s, an interest emerged for novel thyromimetic compounds with lipid-decreasing activity, but without cardiovascular effects. It was eventually found that the TH analogs with an altered side group of the inner iodophenyl ring – including 3, 5, 3’, 5’-tetraiodothyroacetic acid (tetrac) and 3, 5, 3’-triiodothyroacetic acid (triac) (10nM) – failed to stimulate INa in neonatal rat myocytes (Huang et al., 1999). Similarly, they had no effect on the striated muscle SERCA at a concentration of 10 nM (Warnick et al., 1993). Consistently, in a rabbit myocardium preparation no significant change was produced by tetrac, whereas triac (10 nM) depressed SERCA activity (Rudinger et al., 1984). Furthermore, the effects of Tetrac on cardiac hypertrophy were dampened as compared to T4. Tetrac was less efficient in the activation of D2 and in the expression of the SERCA 2a and α-MHC genes, although it proved more potent than T4 in suppressing TSH in isolated pituitary gland (Lameloise et al., 2001).
It has been later ascertained that tetrac and triac are endogenous compounds, obtained by T4 and T3 decarboxylation and deamination (Hansen et al., 2016; Senese et al., 2014). While it is usually assumed that decarboxylation is catalyzed by the ubiquitous enzyme aromatic amino acid decarboxylase, this view has recently been challenged (Hoefig et al., 2012). Triac has been reported to be transported across the plasma membrane of neonatal rat cardiomyocytes, where it reaches nuclear TRs (Verhoeven et al., 2002). Of note, triac shows preferential binding for the β-isoform of TRs, whereas TRα1 is predominant in the myocardium. This can yield clinical benefit whenever the therapeutic aim is represented by TR β effects (e.g. metabolic effects) with limited stimulation of the heart (Wu et al., 2005).
Another relevant thyroacetic acid is TA1. It has been detected in brain as an endogenous compound (Musilli et al., 2014), and it is the major catabolite produced in most cell types after administration of exogenous T1AM, by the action of either monoamine oxidases or semicarbazide-sensitive amine oxidases. In particular TA1 is apparently the end product detected in cardiomyocytes and in perfused rat hearts exposed to exogenous T1AM (Saba et al., 2010). While administration of exogenous TA1 in mice produced significant neurological and metabolic effects (Laurino et al., 2015; Musilli et al., 2014), single (50 mg/kg) and repeated (5mg/kg for 7 days) intraperitoneal administration of TA1 in mice revealed no cardiovascular action (Hoefig et al., 2015). Notably, the dosages used were ineffective despite being in the pharmacological range. In the
heart TA1 can be therefore considered as an inactivation product, which acts as a brake in respect to THs and their metabolites.
3. Conclusions
THM represent a novel branch of TH signaling and have been shown to produce significant functional effects. As far as cardiac actions are concerned, T2, tetrac and triac are able to elicit weak thyromimetic effects, while TA1 appears to be ineffective. On the other hand, exogenous T1AM produces negative inotropic and chronotropic effects and is able to increase the resistance to ischemia-reperfusion injury. However, several crucial questions must still be addressed to gain a better insight into the physiological relevance of the described findings. It is still unclear whether THM are produced in cardiomyocytes or are obtained from the circulation, and their endogenous concentrations are uncertain. Particularly, the subcellular distribution of T1AM is unclear and therefore its concentration at receptor level remains unknown. Further research is also necessary to identify the specific binding sites and molecular pathways involved in the cardiac actions of T1AM and other THM. Unraveling these issues might provide a novel insight into the role of TH signaling in modulating cardiac function and possibly open new therapeutic opportunities.
Conflict of interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding: RZ was partly supported by Fondazione Cassa di Risparmio di Lucca.
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