Impact of hyperthyroidism on cardiac hypertrophy

in Endocrine Connections

Correspondence should be addressed to M L M Barreto-Chaves: mchaves@usp.br

The cardiac growth process (hypertrophy) is a crucial phenomenon conserved across a wide array of species and is critically involved in the maintenance of cardiac homeostasis. This process enables an organism to adapt to changes in systemic demand and occurs due to a plethora of responses, depending on the type of signal or stimuli received. The growth of cardiac muscle cells in response to environmental conditions depends on the type, strength and duration of stimuli, and results in adaptive physiological responses or non-adaptive pathological responses. Thyroid hormones (TH) have a direct effect on the heart and induce a cardiac hypertrophy phenotype, which may evolve to heart failure. In this review, we summarize the literature on TH function in the heart by presenting results from experimental studies. We discuss the mechanistic aspects of TH associated with cardiac myocyte hypertrophy, increased cardiac myocyte contractility and electrical remodeling, as well as the associated signaling pathways. In addition to classical crosstalk with the sympathetic nervous system (SNS), emerging work pointing to the new endocrine interaction between TH and the renin-angiotensin system (RAS) is also explored. Given the inflammatory potential of the angiotensin II peptide, this new interaction may open the door for new therapeutic approaches which target the key mechanisms responsible for TH-induced cardiac hypertrophy.

Abstract

The cardiac growth process (hypertrophy) is a crucial phenomenon conserved across a wide array of species and is critically involved in the maintenance of cardiac homeostasis. This process enables an organism to adapt to changes in systemic demand and occurs due to a plethora of responses, depending on the type of signal or stimuli received. The growth of cardiac muscle cells in response to environmental conditions depends on the type, strength and duration of stimuli, and results in adaptive physiological responses or non-adaptive pathological responses. Thyroid hormones (TH) have a direct effect on the heart and induce a cardiac hypertrophy phenotype, which may evolve to heart failure. In this review, we summarize the literature on TH function in the heart by presenting results from experimental studies. We discuss the mechanistic aspects of TH associated with cardiac myocyte hypertrophy, increased cardiac myocyte contractility and electrical remodeling, as well as the associated signaling pathways. In addition to classical crosstalk with the sympathetic nervous system (SNS), emerging work pointing to the new endocrine interaction between TH and the renin-angiotensin system (RAS) is also explored. Given the inflammatory potential of the angiotensin II peptide, this new interaction may open the door for new therapeutic approaches which target the key mechanisms responsible for TH-induced cardiac hypertrophy.

Introduction

Thyroid hormones (TH) have a significant impact on the entire organism. However, it has been well documented that the heart is the main and the most important target of TH actions. Thus, variations in TH circulating levels are associated with the development and progression of cardiovascular diseases (1, 2, 3, 4). Cardiac hypertrophy, broadly defined as an enlargement of the heart, occurs as a consequence of high levels of TH and may predispose individuals to heart failure (5, 6, 7, 8). Cardiac hypertrophy, driven by TH, is triggered by both direct action on cardiac cells and indirect mechanisms through interaction with other endocrine systems, such as the sympathetic nervous system (SNS) and the renin-angiotensin system (RAS) (9, 10) amongst others.

Accordingly, the importance of exploring the mechanistic aspects of TH action which lead to cardiac hypertrophy and its consequences for cardiac function, highlighting the molecular pathways involved in this process, in order to identify possible novel therapeutic targets, is clear. In this context, this review will describe the basic aspects of TH action, focusing on the molecular and cellular mechanisms associated with cardiac hypertrophy, and the contribution of the RAS as an important mediator of these effects.

Thyroid hormones

Triiodothyronine (T3) and thyroxine (T4) are the major TH produced by follicular cells of the thyroid gland, and they are bound to thyroglobulin protein until their release into the circulation. The synthesis of TH depends on the oxidation of dietary iodine, followed by iodination of tyrosine molecules and their coupling, forming T3 and T4. The main secreted hormone is T4, which is converted by deiodinases to T3 and other metabolites to act on virtually every cell of the organism, regulating basal metabolism and other important functions. Thyroid gland function is regulated by a classical negative feedback mechanism along the hypothalamus-pituitary-thyroid axis, where the hypothalamus produces thyrotropin-releasing hormone (TRH), which acts on the pituitary gland to promote thyroid stimulating hormone (TSH) release (11, 12, 13). TSH, in turn, binds to receptors on thyroid follicular cells promoting the production and release of T4/T3 in the circulation. These hormones, when in their free form, act on receptors in the hypothalamus and the pituitary gland, balancing the production of TRH and TSH, and reducing the release of more TH (14, 15).

Although the thyroid gland is under strict regulatory control in the production and secretion of its hormones, there are conditions that can induce an imbalance of circulating TH levels. Graves’ disease, TSH-secreting adenomas and toxic multinodular goiter are some examples of disorders that can lead to hyperthyroidism (16). In this context, overt hyperthyroidism is characterized by high levels of T3 and T4, and decreased TSH levels. However, the most usual type of hyper­thyroidism observed in medical practice is the subclinical condition, characterized by decreased TSH associated with T3 and T4 levels within the reference values (17, 18). While overt hypothyroidism is characterized by elevated TSH levels and low circulating TH levels, subclinical hypothyroidism is diagnosed when TSH levels are elevated above the reference range but TH levels are normal. The etiology of both forms of hypothyroidism is most often caused by chronic autoimmune thyroiditis, therapies that destroy thyroid tissue and drugs that damage thyroid function (19).

From a mechanistic point of view, circulating TH reach their target tissues and cross the plasma membranes of cells through multiple tissue-specific transporters (20), such as monocarboxylate transporter 8 (MCT8) and 10 (MCT10), and proteins from the organic anion transporting polypeptide (OATP) family (21, 22, 23, 24). T4 is converted to T3, diiodothyronine (T2) or reverse T3 (rT3) by tissue deiodinases (D1, D2 or D3). D1 and D2 are responsible for the production of more than 70% of circulating T3 from T4 (25). D2 is located in the endoplasmic reticulum and is very active in the placenta, cardiac muscle and pituitary gland, where it helps to mediate the TSH production negative feedback loop (26, 27). D1 is found in the plasma membrane of various cells and also catalyzes the formation of rT3 and T2 (25, 26). D3, in turn, is an enzyme normally expressed in the central nervous system (CNS) and placenta, and is found in the cellular plasma membrane; however, in ischemic situations D3 migrates to the nuclear membrane, where it inactivates T4 and T3, thereby reducing cellular metabolism (28, 29, 30). Polymorphisms in these enzymes, or other diseases, may increase or reduce their activities, altering TH levels, and lead to systemic disorders (31, 32, 33).

There are multiple mechanisms by which TH play their role on cells, some mechanisms cause effects within seconds or minutes, while other mechanisms which depend on gene transcription take longer (minutes to hours) (34, 35, 36, 37). Direct binding of TH to receptors located on mitochondria or in the cellular plasma membrane (e.g. integrin αVβ3) triggers the activation of intracellular signaling cascades and rapidly modulates the activity of ionic channels, although later effects on gene expression may result from the activation of these cascades (38, 39, 40, 41, 42). Some of the effects of TH depend on binding to specific receptors for thyroid hormones (the thyroid hormone receptors (TR)), which can be located both in the cell cytoplasm and in the nucleus. When activated in the cytoplasm, the TH-TR complex interacts with kinases and phosphatases, and modulates their pathways, such as the PI3K pathway, without the need for DNA binding (43, 44).

Many of the actions triggered by TH occur in the cell nucleus and result from the binding of TH to TR, and the interaction of this complex with DNA to promote the expression of target genes. The canonical mechanism is T3 binding to TR: T3 is considered the predominant active form of TH because of its higher affinity for TR (ten-fold higher than T4) (34, 35, 36). There are two known TR isoforms (TR-α and TR-β), which usually dimerize with steroid hormone receptors (such as retinoic acid receptor (RXR), forming the TR-RXR complex), or, to a lesser extent, as a homodimer (45, 46, 47). These complexes have high affinity for specific DNA sequences called thyroid responsive elements (TRE) and remain attached to them, generally suppressing the expression of their target genes, whereas binding of T3 to this complex stimulates transcription (48, 49). However, the TH-TR complex may not require direct DNA connection to exert its effects; this complex can interact with transcription factors or other proteins associated with chromatin which, in turn, will promote the modulation of gene expression independent of direct TH-TR complex DNA binding.

It is important to note that regardless of the mechanism of action, the combination of all the effects triggered by TH may activate several cellular pathways and determine different manifestations associated with cardiac dysfunction, for example, in the development of cardiac hypertrophy which precedes heart failure.

Hyperthyroidism and the heart

The main target of T3 is the heart, in which it promotes increased contractility and heart rate, leading to increased cardiac output. Thus, although hyperthyroidism induces a decrease in peripheral vascular resistance, its effect in raising cardiac output leads to the arterial hypertension frequently observed clinically. Such alterations contribute to a process of growth (cardiac hypertrophy), initially considered physiological or adaptive, which is critically involved in the maintenance of cardiac homeostasis and occurs as a result of increased cardiac demand. In this case, the cardiac hypertrophy observed in hyperthyroidism is characterized by: (1) ventricular wall thickening (concentric hypertrophy), due to the addition of sarcomeres in parallel within the cardiomyocyte; (2) increased contraction force, as a result of the modulation of pathways that tend to increase calcium uptake; and (3) increased relaxation velocity, due to increased calcium uptake by the sarcoplasmic reticulum during diastole. However, the long-term effects of T3 may result in cardiac hypertrophy as a consequence of dysfunction, also classified as pathological hypertrophy, which leads to cardiac remodeling and heart failure.

Although an increase in left ventricular mass has been observed in patients with hyperthyroidism, even with antithyroid treatment (50), a more recent study demonstrated that cardiovascular dysfunction associated with hyperthyroidism can be attenuated by treatment with antithyroid drugs and can be reversible after total thyroidectomy (51). In addition, the combination of antithyroid therapy and beta blockers, to control heart rate, prevents hemodynamic overload and cardiac remodeling leading to complete recovery from heart failure (52).

Supporting clinical findings, experimental data also demonstrated that antithyroid treatment significantly prevented the cardiac dysfunction induced by T4 in mice. In addition, the reversibility of cardiac pathology was also observed after 2 weeks of discontinuation of treatment with T4, including cardiac hypertrophy (53).

TH in cardiac cells

In cardiac tissue, TH exert their effects in cardiomyocytes, and other cardiac non-myocyte cells such as fibroblasts, endothelial cells, vascular smooth muscle cells and hematopoietic-derived cells. Cardiomyocytes correspond to two-thirds of the heart volume and express ten-fold more TRs than fibroblasts (44), which make them more responsive to TH action and a protagonist of cardiac hypertrophy.

In cardiac fibroblasts, although TH increase the expression of TGF-β1, a pro-fibrotic marker, TH also promote a decrease in type 1 collagen gene expression, the major fibrillar collagen in the heart (54, 55, 56). In fact, different studies in the literature have shown that TH induce cardiac hypertrophy without increasing collagen deposition (57, 58, 59). This antifibrotic role of TH is already well known, and the potential of these hormones as a alternative treatment for fibrosis in the heart has recently been studied (55, 60).

In the vasculature, TH act on both endothelial cells and smooth muscle cells, promoting an increase in the production of nitric oxide, a decrease in the proliferation of vascular smooth muscle cells and an improvement in angiogenesis (43, 61, 62, 63, 64). In this way, TH modulate vascular remodeling and contribute to the maintenance of endothelial function.

It is important to note that, in the human and murine heart, approximately 5% of non-myocytes are hematopoietic-derived cells (65). Additionally, resident and recruited immune cells respond earlier to cardiac injury, and coordinate cardiomyocyte and non-cardiomyocyte responses during hypertrophy and remodeling (66). However, although some studies have investigated the effects of TH on various types of immune cells (67, 68, 69), the impact of immune cells on the cardiac actions of TH remains to be clarified.

Regarding the role of TH at the cellular level in the context of cardiomyocyte hypertrophy, different mechanisms have been described in the literature. In general, these processes are triggered by the action of TH, which lead to an increase in the expression of sarcoplasmic reticulum Ca2+-ATPase (SERCA2) and ryanodine receptors associated with a decrease in phospholamban, which results in faster systole and diastole (positive inotropism and lusotropism, respectively) (8, 70, 71, 72, 73). Alpha myosin heavy chain (α-MHC) is upregulated by TH while beta myosin heavy chain (β-MHC) is downregulated, which significantly enhances the contractile function of cardiac papillary muscle (8, 74, 75, 76). Additionally, actin and troponin I levels are also increased by TH in the heart (77) (Fig. 1). Interestingly, some of those TH-responsive genes are modulated by microRNAs (miR). Part of the decrease in β-MHC levels observed in hyperthyroidism is due to overexpression of miR-208a (78, 79, 80) and miR-27a (81), while increased SERCA2 levels are regulated by miR-133 (82). In addition, TH increase the expression and activity of Na+/K+-ATPase channels and beta-adrenergic receptors in cardiomyocytes, which leads to greater sensitivity of the heart to sympathetic stimulation, contributing to the positive inotropic effect (77, 83, 84, 85, 86, 87, 88). These alterations may contribute to the tachycardia events and atrial fibrillation that are often associated with hyperthyroidism (89).

Figure 1
Figure 1

Some examples of thyroid hormones action on cardiomyocytes, which are upregulated in hyperthyroidism. Thyroid hormones (TH) might interact with cell surface receptors, such as integrin aVb3, to trigger the fast activation of cytoplasmic kinases, or it may enter the cell with the help of transporters such as MCT8. In the cytosol, much of T4 (tyroxine) is converted to T3 (triiodothyronine) by the action of the enzyme D2 (type 2 deiodinase). T3 then interacts with mitochondrial or cytoplasmatic receptors, affecting the activity of ion channels and the production of reactive oxygen species (ROS). This hormone also migrates to the nucleus and binds to thyroid hormone receptors (TR), forming a complex with high affinity for DNA-coupled thyroid response elements (TRE), although the T3-TR complex may interact with other DNA-bound proteins without the need to directly bind to chromatin to play its role. Thus, the transcription of several target genes is modulated, followed by protein synthesis, which ultimately results in cell hypertrophy.

Citation: Endocrine Connections 9, 3; 10.1530/EC-19-0543

Moreover, diverse intracellular signaling pathways are rapidly activated by T3 and mediate cardiomyocyte growth, as occurs in the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway (59, 90). These actions may also be triggered by membrane integrin αVβ3 (38), which has two TH binding sites: S1, which recognizes T3 and activates the PI3K pathway; and S2, which binds to both TH (despite having much higher affinity for T4) and activates the mitogen activated protein kinase (MAPK) pathway (40, 41, 42). Another important signaling pathway involved with TH-induced cardiomyocyte hypertrophy is adenosine mono phosphate-activated protein kinase (AMPK) signaling. AMPK is a sensor of intracellular adenosine nucleotide levels that is activated when ATP synthesis decreases and AMP or ADP levels increase. In response, AMPK activates catabolic pathways to generate more ATP and inhibits anabolic pathways, such as those involved in protein synthesis. In T3-treated cardiomyocytes, AMPK silencing induces increased hypertrophy, while AMPK stimulation attenuates this process (91), indicating its important cardioprotective role in hyperthyroid hearts.

Additionally, pathways involved in inflammation have also been related to the development of TH-induced cardiac hypertrophy. In this context, our group recently demonstrated that acute T3 treatment increased the expression of S100A8 (also known as calgranulin A), a calcium binding protein that when secreted to the extracellular space binds to toll-like 4 membrane receptors (TLR4), resulting in the recruitment of myeloid differentiation protein 88 (Myd88) and activation of nuclear factor-κB (NFkB). Inhibition of Myd88 and NFkB are able to attenuate cardiomyocyte hypertrophy, highlighting the involvement of this pathway in T3-induced hypertrophy (92).

The activation of inflammatory pathways is closely associated with cellular redox state. Regarding the heart, there is evidence which demonstrates increased free radical production and decreased mitochondrial antioxidant capacity in hyperthyroidism, resulting in cardiac oxidative stress (93, 94). The accumulation of reactive oxygen species (ROS) in the hyperthyroid heart seems to be crucial to the development of T3-induced cardiac hypertrophy, as antioxidant treatment with vitamin E attenuated cardiomyocyte growth (95).

While the activation of several pathways related to protein synthesis has been associated with the hypertrophic effects of TH, proteolysis related pathways also appear to play an important role in this process. Recently, we have demonstrated increased expression of the proteasome in the hearts of hyperthyroid rats (96). Both catalytic (20SPT) and regulatory subunits (19SPT) of the constitutive proteasome, together with immunoproteasome subunits, were upregulated in rats treated with T3. Furthermore, ATP-dependent chymotrypsin-like activity (26SPT) was increased in cardiac tissue from hyperthyroid rats and in isolated cardiomyocytes treated with T3, which may be involved in the maintenance of protein quality control and the regulation of T3-induced cardiac hypertrophy (96).

Interaction of TH with other endocrine systems

Besides the direct actions of TH in the cardiomyocyte, cardiac hypertrophy induced by T3 is also a result of indirect effects of this hormone. An important contribution of the SNS has long been demonstrated in the development of tachycardia, increased force and velocity of cardiac contraction, and cardiac hypertrophy initiation in hyperthyroidism. Thus, it has been demonstrated that treatment with the beta-adrenergic blocker propranolol inhibited T3-induced cardiac hypertrophy and increased heart rate (10). Plasma and urine levels of catecholamines are not altered in hyperthyroidism, which indicate that some T3 effects are mediated by an increased responsiveness and sensitivity of cardiac tissue to sympathomimetic stimuli (97). This increased sympathetic sensitivity is due to an increase in the number of adrenergic receptors in the hyperthyroid heart (98). Thus, the administration of a beta-adrenergic receptor antagonist to patients with hyperthyroidism is often used by clinicians to attenuate heart rate, systolic blood pressure and other cardiovascular manifestations (18, 99). However, in some cases the use of beta-adrenergic antagonists is contraindicated, which demonstrates the need for new therapeutic targets.

In addition to the increased cardiac beta-adrenergic sensitivity observed in hyperthyroidism, the RAS has been recognized in the last two decades as a significant mediator of the cardiovascular actions of TH, and our studies have contributed to the understanding of the crosstalk between TH and the RAS. The RAS is an important endocrine regulator of cardiovascular homeostasis, classically acting in the control of blood pressure and extracellular fluid volume (100). Alterations in the levels of peptides that constitute the RAS are closely related to cardiovascular function impairment, and for this reason several members of the RAS have been used as a target for the development of therapeutic drugs.

In the classical RAS, renin (an aspartyl protease produced in juxtaglomerular cells) forms angiotensin I (Ang I) by cleavage of the N-terminal portion of hepatic angiotensinogen (AGT). Ang I is converted into angiotensin II (Ang II) by the action of ACE (Ang I converting enzyme), an endothelial peptidase which removes two C-terminal amino acids (101, 102). Ang II is an octapeptide which binds to two specific G-protein-coupled receptors, AT1R and AT2R, to perform its biological activity, as illustrated in Fig. 2.

Figure 2
Figure 2

Involvement of the RAS in cardiac hypertrophy induced by TH. AT1R activation triggers TH-mediated cardiac hypertrophy by activating the miR-208a/α-MHC, Akt/GSK3β/mTOR and NFkB pathways, and by downregulating miR-133. Additionally, AT2R contributes to cardiac growth in hyperthyroid rats by participating in Akt and TGF-β activation.Increased levels of Ang-(1–7) prevents the development of T3-induced cardiac hypertrophy by blocking GSK3β/NFATc3 activation via the MAS receptor. AGT, angiotensinogen; Ang I, angiotensin I; Ang II, angiotensin II; Ang-(1–9), angiotensin-(1–9); Ang-(1–7), angiotensin-(1–7); ACE, angiotensin I converting enzyme; ACE2, angiotensin II converting enzyme; AT1R, angiotensin II receptor type 1; AT2R, angiotensin II receptor type 2.

Citation: Endocrine Connections 9, 3; 10.1530/EC-19-0543

Although the RAS has been considered as an endocrine system dependent on renal renin, over the years accumulating evidence suggests that different tissues are able to locally synthesize some of the RAS components, including Ang II (103). In fact, it has been demonstrated that AGT, ACE, AT1R and AT2R are expressed in the heart, enabling the local synthesis and action of Ang II in this organ (104, 105, 106). In addition, it is important to emphasize that most cardiac Ang I and Ang II peptides are produced locally rather than derived from the blood, indicating that this endocrine system is clinically relevant (107).

TH regulate the activity of the RAS in different tissues, and therefore several studies have been conducted to understand the crosstalk between these two endocrine systems, especially in thyroid gland disorders (9, 108). In this context, experimental hyperthyroidism is associated with increased levels of renin, Ang II, AT1R and AT2R in the heart (109, 110, 111, 112). Additionally, it has been shown that a critical RAS contribution to cardiac hypertrophy is observed in hyperthyroidism, as the inhibition of Ang II activity by AT1R/AT2R blockers or ACE inhibition totally prevents the development of cardiac hypertrophy in vivo and in vitro (10, 51, 110, 113, 114, 115, 116, 117). AT1R silencing using a siRNA or AT1R blockade with a pharmacological antagonist (losartan) completely abolished TH-induced activation of the miR-208a/α-MHC, Akt/GSK3β/mTOR and NFkB signaling pathways, together with the downregulation of miR-133. These mechanisms have been shown to play a key role in the development of T3-induced cardiac hypertrophy (78, 82, 59, 92, 116). Concerning AT2R, Carneiro-Ramos and collaborators demonstrated that blockage of this receptor also prevents TH-mediated cardiac hypertrophy in vivo and in vitro, by preventing Akt activation (117) (Fig. 2). Furthermore, TH increase transforming growth factor beta (TGF-β) expression in cardiac tissue by AT2R stimulation, which may be involved in TH-mediated cardiac hypertrophy (58) (Fig. 2).

In addition to the peptides previously described, in the late 1980s the classical view of the RAS was expanded after discovering a new heptapeptide, angiotensin-(1–7) (Ang-(1–7)), which activates the G-protein-coupled receptor MAS (118, 119). Ang-(1–7) is formed from Ang II by the enzymatic action of the carboxypeptidase ACE2 (Ang II converting enzyme) or from Ang I by an ACE-independent pathway (120, 121, 122) (Fig. 2). In the hyperthyroid state, an upregulation of Ang-(1–7), ACE2 activity and the MAS receptor in the heart was demonstrated, with no changes in the plasma levels of Ang-(1–7) (123). Contributing to these data, recently it was shown that elevated circulating levels of Ang-(1–7) prevented T3-induced cardiac hypertrophy by attenuating the glycogen synthase kinase 3 beta/nuclear factor of activated T-cells (GSK3β/NFATc3) signaling pathway (124) (Fig. 2).

Considering that cardiac hypertrophy may represent an important risk factor for the progression of cardiovascular disease, understanding the crosstalk between the RAS and TH is clearly clinically important; new pharmacological tools to reduce the cardiac complications observed in hyperthyroidism are required, especially in patients in whom beta-adrenergic antagonists are contraindicated.

Conclusion and future perspectives

Several key mediators of TH-induced cardiac hypertrophy have been identified from animal studies. However, despite significant progress in understanding the molecular mechanisms that accompany TH-induced cardiac hypertrophy, further studies are required in order to understand the complex level of communication between TH and other systems. In this context, the influence of hypoxia in the microenvironment of TH-induced cardiac hypertrophy and the crosstalk between TH, hypoxia and inflammation signaling remain to be clarified, as does the potential role of TH in the early and long-term cardiac angiogenesis process.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work was supported by São Paulo Research Foundation (FAPESP – grant numbers: 2016/13896-0), National Council of Scientific and Technological Development (CNPq – grants number: 305182/2014-5 and 302022/2019-8) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001. Part of this manuscript was previously presented at the 21st Congress of European Society of Endocrinology in Lyon, France.

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    Some examples of thyroid hormones action on cardiomyocytes, which are upregulated in hyperthyroidism. Thyroid hormones (TH) might interact with cell surface receptors, such as integrin aVb3, to trigger the fast activation of cytoplasmic kinases, or it may enter the cell with the help of transporters such as MCT8. In the cytosol, much of T4 (tyroxine) is converted to T3 (triiodothyronine) by the action of the enzyme D2 (type 2 deiodinase). T3 then interacts with mitochondrial or cytoplasmatic receptors, affecting the activity of ion channels and the production of reactive oxygen species (ROS). This hormone also migrates to the nucleus and binds to thyroid hormone receptors (TR), forming a complex with high affinity for DNA-coupled thyroid response elements (TRE), although the T3-TR complex may interact with other DNA-bound proteins without the need to directly bind to chromatin to play its role. Thus, the transcription of several target genes is modulated, followed by protein synthesis, which ultimately results in cell hypertrophy.

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    Involvement of the RAS in cardiac hypertrophy induced by TH. AT1R activation triggers TH-mediated cardiac hypertrophy by activating the miR-208a/α-MHC, Akt/GSK3β/mTOR and NFkB pathways, and by downregulating miR-133. Additionally, AT2R contributes to cardiac growth in hyperthyroid rats by participating in Akt and TGF-β activation.Increased levels of Ang-(1–7) prevents the development of T3-induced cardiac hypertrophy by blocking GSK3β/NFATc3 activation via the MAS receptor. AGT, angiotensinogen; Ang I, angiotensin I; Ang II, angiotensin II; Ang-(1–9), angiotensin-(1–9); Ang-(1–7), angiotensin-(1–7); ACE, angiotensin I converting enzyme; ACE2, angiotensin II converting enzyme; AT1R, angiotensin II receptor type 1; AT2R, angiotensin II receptor type 2.

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