Thyroid Hormones (T3 and T4) and Their Effects on the Cardiovascular System

Abstract

Thyroid hormones (thyroxine, triiodothyronine) have a metabolic effect on many tissues and systems in the organism. Therefore, in case of deficiency or excess of these hormones, some problems arise. The decrease in the effect of these hormones in the peripheral target tissue is called hypothyroidism, the picture characterized by excessive secretion of the thyroid gland or being of non-thyroid origin is called hyperthyroidism. Thyroid hormone disorders are common in the world. Knowing the functions of thyroid hormones, which have such important effects on the organism, is important in developing treatment options for the problems to be encountered. In the literature reviews, it has been stated that thyroid hormones have some effects such as heart rate, myocyte contraction, blood pressure, plasma lipid level, and thrombogenesis. In line with this information, the presented section has tried to explain how the mechanism of the effects of thyroid hormones on the cardiovascular system.

1. Introduction

The thyroid gland, which is the largest of the endocrine glands and is located in the right and left lobes on both sides of the end of the larynx and the beginning of the trachea, is histologically composed of many spherical follicles. The space in the middle of the follicle surrounded by a single layer of epithelial cells is filled with a substance called colloid. The main substance of the colloid is a large glycoprotein, namely thyroglobulin, which also contains the gland hormones like thyroxine (T4) and triiodothyronine (T3) [1]. These hormones are secreted as a result of stimulation of the thyroid gland by the thyroid-stimulating hormone (TSH) released from the pituitary [2]. The thyroid gland shows its effects on the target tissue through these two hormones. Of these hormones, T3 has a much stronger effect than T4. T4 is converted to T3 by monodeiodinization in the periphery [3]. T3 exerts its effects at nuclear and nonnuclear levels. Its effects at the nuclear level are through the regulation of gene expression [4]. These hormones released from the thyroid gland affect metabolic processes in almost all tissues [5, 6, 7, 8]. Insufficient or excessive secretion of these hormones causes many problems in the organism. As a result of various studies, it has been reported that the effects of thyroid hormones on the cardiovascular system are very important and prominent [9]. It shows this effect in two ways: direct and indirect. In line with this information, in the presented section, the synthesis of thyroid hormones, their mechanisms of action, and their effects on the cardiovascular system and the mechanism of these effects will be discussed.

2. Thyroid hormones

Thyroid hormones are thyroxine (T4) and 3,5,3′ triiodothyronine (T3) and these hormones are released into the blood by being released from the thyroid gland. These hormones are very important for normal growth and development and the normal functioning of metabolism. In addition to these hormones, the calcitonin hormone, which is involved in Ca metabolism, is also released from parafollicular C cells in the thyroid gland [7].

2.1 Synthesis of thyroid hormones

The release of thyroid hormones from the thyroid gland is under the control of the TRH hormone released from the hypothalamus. TRH released from the hypothalamus stimulates the pituitary gland to release TSH. TSH released from the pituitary stimulates the thyroid gland and ensures the release of hormones from here [10]. Thyroid hormones are attached to the thyroglobulin molecule in the thyroid gland. These hormones, which are stored in the thyroid gland, are given to the blood circulation when needed. In general, the synthesis of thyroid hormones consists of 5 stages. These stages are as follows, in order: (1) uptake of iodine ion into the gland, (2) oxidation of iodine and iodination of the tyrosyl groups of thyroglobulin, (3) coupling of iodotyrosine residues with ether bonds (coupling) to form iodothyronines, (4) proteolysis of thyroglobulin and thyroxine (T4). Release of T3) into the blood, (5) conversion of thyroxine to triiodothyronine in both the thyroid gland and peripheral tissues [7, 11]. When the T3 and T4 hormones released into the blood under the control of these hormones reach a certain level, they stop the release by having a feedback effect on the hypothalamus and pituitary gland [12].

Although T3, one of the thyroid hormones, is released from the thyroid gland, the source of 80% of the circulating T3 is T3, which is formed as a result of the metabolism of T4 in peripheral tissues. The enzyme that provides the transformation in question is iodothyronine-5′-deiodinase. The place where the transformation takes place the most is the liver. The source of T3 used in many peripheral tissues is the hormone released as a result of this transformation. Unlike these tissues, locally synthesized T3 is used in the brain and pituitary gland. When thyroid hormones are released into the blood, they are transported in the blood by noncovalent binding to plasma proteins. At the beginning of these transporters is thyroxine-binding globulin (TBG). T4 binds to this binder with high affinity, whereas T3 has less affinity. T4 also binds to transthyretin (transthyretin: thyroxine-binding prealbumin) (Figure 1) [7, 13, 14].

Figure 1.

Control of synthesis of thyroid hormones [7].

2.2 Mechanism of action of thyroid hormones

Considering the mechanisms of action of thyroid hormones in the cell, T3 is clamped to high-affinity nuclear receptors on the cell surface, which then binds to a specific DNA sequence (thyroid hormone response element: TRE) in the promoter/regulatory regions of specific genes. In this way, T3 modulates gene transcription and ultimately protein synthesis. The binding of T3 to the receptor can activate gene transcription by removing suppression. The interaction of hormones with their receptors can cause direct stimulating or suppressive effects. Although T4 also binds to the aforementioned receptors, it shows less affinity than T3. In addition, despite its ability to bind to nuclear receptors, T4 does not have a gene transcription-modifying effect [15]. Therefore, T4 appears to be more of a prohormone, and the effects of TH are considered to be mainly through T3 [16]. TH also exerts some of its effects on receptors in mitochondria. These hormones increase the oxidative metabolism of mitochondria, oxygen consumption, and ATP formation in some cell types (Figure 2) [17, 18].

Figure 2.

Mechanism of action of thyroid hormones on target cell [7].

3. Effects of thyroid hormones on the cardiovascular system

Thyroid hormone (TH) receptors (TRs) are located in the myocardium and vascular endothelium, so changes in circulating TH concentration have an effect on cardiac and vascular functions. In patients with hypo- or hyperthyroidism, cardiovascular (CV) and hematological manifestations occur. Minor changes in TH concentration may have an adverse effect on the CV system, and subclinical thyroid dysfunction may result in a 20–80% increase in the risk of vascular morbidity and mortality [19, 20, 21].

3.1 Thyroid hormone and heart rate

Heart rate is an important mechanism in the regulation of the cardiac output, which specifically determines the cardiac ejection rate. It also affects systolic and diastolic functions [22]. Considering the relationship between thyroid hormone and heart rate, studies have shown that thyroid hormone has a consistent positive chronotropic effect and causes resting sinus tachycardia [23].

3.2 Effect of thyroid hormones on cardiac myocytes

The genomic effects of TH are mediated by TH nuclear receptors in the cell. Protein receptors bind to T3 with more than 10-fold greater affinity than T4 [24]. In mammals, there are two isoforms of these receptor proteins, a and b (TRa and TRB). TRa and TRB activate the expression of positively regulated genes in the presence of T3 and suppress expression in their absence. It has been determined that the TRa1 isoform plays an important role in the regulation of cardiac genes. It contains myosin heavy chain an (a-MHC) and myosin heavy chain b (b-MHC) as contractile apparatus of cardiac myocytes. The fast myosin a-MHC and the slow myosin b-MHC are positively and negatively regulated by T3. Cardiac contractility is further regulated by several important cardiac proteins, including sarcoplasmic reticulum calcium adenosine triphosphatase (SERCA2) and its inhibitory counterpart, phospholamban (PLB). SERCA2 functions to pump calcium (Ca2+) ions back into the sarcoplasmic reticulum during the relaxation phase of myofilament contraction. T3 positively regulates SERCA2 while negatively regulating PLB. SERCA2 and PLB are responsible for calcium ion influx into the sarcoplasmic reticulum and subsequent release [25]. Decreased calcium turnover in cardiac myocytes has been reported in hypothyroidism with impaired diastolic function. Other important cardiac genes regulated by TH include those encoding TR proteins themselves, voltage-gated potassium ion (K+) channels, and sodium/calcium ion (Naþ/Ca2+) exchanger (NCX1).TH (both T4 and T3) exerts non-genomic effects on cardiac myocytes and vessels. Non-genomic effects usually occur at the receptor-independent plasma membrane and regulate ion transporter activity [26]. These combined mechanisms at the atrial myocyte level are partly responsible for the heart rate-enhancing effect of T3 [27].

3.3 Effect of thyroid hormones on vascular

When the effects of TH on the vessels are examined, it is seen that the effect occurs at the vascular smooth muscle and endothelial cell levels. TH acts through ion channel activation (Na+, K+, Ca2+) and regulation of specific signal transduction pathways. It also activates the phosphatidylinositol 3-kinase and serine/threonine protein kinase pathways, resulting in nitric oxide production from the endothelium. Thus, it causes a decrease in systemic vascular resistance through its effects on vascular smooth muscle cells [28]. Some studies have shown that TH regulates endothelial nitric oxide production and vascular tone, and patients with hypothyroidism exhibit impaired endothelial function, which is improved by TH replacement therapy [29, 30, 31]. In addition, T3 may produce a vasodilator effect within hours after the application in patients undergoing coronary artery bypass grafting [32]. Similar effects are observed when patients with chronic heart failure are treated with intravenous T3 [33]. T3, therefore, has the unique pharmacological properties of an indicator acting primarily on diastolic dysfunction. TH does not have vasodilator effects in the pulmonary vasculature or systemic vasculature [34].

3.4 Cardioprotective effect of thyroid hormones

THs are involved in cardioprotection through the activation of cytoprotective mechanisms, stimulation of cell growth, neoangiogenesis, and metabolic adaptation. Recent experimental studies using the ischemia/reperfusion rat model have shown that TH has multiple protective effects, particularly on mitochondria. TH is a regulator of the tumor suppressor p53, which is activated during acute myocardial infarction (AMI) and enhances the mitochondrial apoptosis pathway [35]. This promotes p53 accumulation and, therefore, increases mitochondrial dysfunction and BCL-2-like protein 4 activation, leading to the prolongation of myocardial cell loss [36]. T3 treatment counteracts the reduction in miR-30a levels, thereby limiting p53 activation and the cascade that leads to mitochondrial damage and cell death in the AMI border region [37]. In addition, T3 treatment preserves the expression of hypoxia-inducible factor 1-alpha, whose protective effect against reperfusion injury is mediated by inhibiting the mitochondrial opening of permeability passage pores [38]. THs have an antiapoptotic effect on myocytes through activation of phosphatidylinositol 3-kinase/serine/threonine protein kinase and protein kinase C signaling cascades, expression, phosphorylation and translocation of heat shock proteins 70 and 27, and suppression of p38 mitogen [39].

3.5 Thyroid hormones and blood pressure

Considering the effects of hyperthyroidism on blood pressure, it causes hyperdynamic circulation, which causes an increase in cardiac contractility and thus increases heart rate, again with increased preload and decreased systemic vascular resistance (SVR). As a result, cardiac output increases. Although hyperthyroidism can increase systolic blood pressure, the net effect depends on the balance between increased cardiac output and decreased SVR [40, 41]. Endothelium-dependent vasodilation is lower in patients with severe hypothyroidism and SCH [42] and improves with levothyroxine therapy, as is the pulse-wave rate [43, 44], a surrogate measure of arterial stiffness. Various factors possibly contribute to arterial stiffness and endothelial dysfunction in SCH and hypothyroidism, including hyperlipidemia and a proinflammatory state [45, 46, 47]. Both hyperlipidemia and thyroid antibodies are thought to reduce endothelial nitric oxide synthase expression and thus impair vasodilation.

3.6 Thyroid hormones and hyperlipidemia

Hyperthyroidism lowers cholesterol levels, which reverses when euthyroidism is reached. Hypothyroidism is associated with a small but significant increase in lipid parameters [38], particularly the elevation of low-density lipoproteins (LDLs) [48]. Hypothyroidism is associated with increased oxidation of LDL, which promotes atherogenesis and improves with treatment [49, 50]. Lipoprotein(a), a stronger marker of atherogenesis, is also increased in overt hypothyroidism and decreased with TH replacement [51, 52]. In hypothyroidism, hyperlipidemia results from a decrease in LDL receptors, resulting in decreased cholesterol clearance from the liver and decreased cholesterol-clearing activity of cholesterol 7α-hydroxylase activated by TH [48]. In addition, thyroid hormones stimulate lipoprotein lipase (LPL), which catabolizes TG-rich lipoproteins, and hepatic lipase (HL), which hydrolyses HDL2 to HDL3 and contributes to the conversion of medium-density lipoproteins (IDL) to LDL. Another effect of T3 is the up-regulation of apolipoprotein AV (ApoAV), which plays an important role in TG regulation. In studies, this situation has been associated with increased ApoAV levels and decreased TG levels.

3.7 Thyroid hormones and thrombogenesis

Overt and SHyper have been associated with increased markers of thrombogenesis (fibrinogen and factor X levels) [53, 54]. Hyperthyroid patients may have higher von Willebrand antigen levels than euthyroid patients, resulting in increased platelet plug formation, decreasing after treatment [55]. Interestingly, a study comparing patients with moderate and severe hypothyroidism with euthyroid controls found that patients with moderate hypothyroidism had reduced fibrinolytic activity and were more susceptible to clot formation, while patients with severe hypothyroidism had increased fibrinolysis and lower tissue plasminogen activator antigen [56]. The effects of TH on platelet function are unclear [55].

4. Conclusion

In conclusion, this section presents the importance of thyroid hormones for the organism and the synthesis steps of these hormones, their transport in the blood, and their effects on the cardiovascular system. The mechanisms of these effects are discussed by reviewing the current literature. This study aims to present current literature information to researchers who will work on this subject.