Thyroid Hormone-induced Cardiac Hypertrophy Research Articles

Hydrogen Attenuates Thyroid Hormone-Induced Cardiac Hypertrophy in Rats by regulating angiotensin II type 1 receptor and NADPH oxidase 2 mediated oxidative stress

Cardiac hypertrophy occurs as a result of high levels of thyroid hormone, which may contribute to heart failure and is closely related to oxidative stress. Hydrogen is a good antioxidant. In this study, we found that intragastric levothyroxine administration for two weeks caused obvious cardiac hypertrophy without reduced systolic function. Additionally, hydrogen inhalation ameliorated the levothyroxine-induced metabolic increase and cardiac hypertrophy in rats. Serum brain natriuretic peptide expression was also attenuated by hydrogen treatment. However, hydrogen had no significant effect on levothyroxine -induced serum troponin I and serum thyroid hormone changes.Hydrogen treatment also reduced the levothyroxine-induced increase in cardiac malondialdehyde, 8-hydroxy-2-deoxyguanosine and serum hydrogen peroxide levels and upregulated superoxide dismutase and glutathione peroxidase activity. Additionally, western blotting results showed that hydrogen inhalation inhibited the expression of cardiac nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), angiotensin II type 1 receptor, sarcoplasmic reticulum Ca2+-ATPase (SERCA2), phospho-phospholamban and α-myosin heavy chain proteins. In conclusion, the present study revealed a protective effect of hydrogen on levothyroxine -induced cardiac hypertrophy by regulating angiotensin II type 1 receptors and NOX2-mediated oxidative stress in rats.

Central Hypothyroidism Impairs Heart Rate Stability and Prevents Thyroid Hormone-Induced Cardiac Hypertrophy and Pyrexia.

Background: Tachycardia, cardiac hypertrophy, and elevated body temperature are major signs of systemic hyperthyroidism, which are considered to reflect the excessive thyroid hormone (TH) action in the respective peripheral tissues. However, recent observations indicate that the central actions of TH also contribute substantially to cardiovascular regulation and thermogenesis. Methods: In this study, we dissect the individual contributions of peripheral TH action versus the central effects in body temperature regulation and cardiovascular functions by taking advantage of mice lacking the TH transporters monocarboxylate transporter 8 (MCT8) and organic anion transporting polypeptide 1C1 (OATP1C1) (M/O double knock-out [dko]), which exhibit elevated serum triiodothyronine (T3) levels while their brain is in a profoundly hypothyroid state. We compared these animals with wild-type (WT) mice that were treated orally with T3 to achieve similarly elevated serum T3 levels, but are centrally hyperthyroid. For the studies, we used radiotelemetry, infrared thermography, gene expression profiling, Western blot analyses, and enzyme linked immunosorbent assays (ELISA) assays. Results: Our analyses revealed mild hyperthermia and cardiac hypertrophy in T3-treated WT mice but not in M/O dko animals, suggesting that central actions of TH are required for these hyperthyroid phenotypes. Although the average heart rate was unaffected in either model, the M/O dko exhibited an altered heart rate frequency distribution with tachycardic bursts in active periods and bradycardic episodes during resting time, demonstrating that the stabilization of heart rate by the autonomic nervous system can be impaired in centrally hypothyroid animals. Conclusions: Our studies unravel distinct phenotypical traits of hyperthyroidism that depend on an intact central nervous system, and provide valuable insight into the cardiovascular pathology of the Allan-Herndon-Dudley syndrome, a condition caused by the lack of MCT8 in humans.

Cardiac ACE2/angiotensin 1-7/Mas receptor axis is activated in thyroid hormone-induced cardiac hypertrophy.

Thyroid hormone (TH) promotes marked effects on the cardiovascular system, including the development of cardiac hypertrophy. Some studies have demonstrated that the renin-angiotensin system (RAS) is a key mediator of the cardiac growth in response to elevated TH levels. Although some of the main RAS components are changed in cardiac tissue on hyperthyroid state, the potential modulation of the counter regulatory components of the RAS, such as angiotensin-converting enzyme type 2 (ACE2), angiotensin 1-7 (Ang 1-7) levels and Mas receptor induced by hyperthyroidism is unknown. The aim of this study was to investigate the effect of hyperthyroidism on cardiac Ang 1-7, ACE2 and Mas receptor levels. Hyperthyroidism was induced in Wistar rats by daily intraperitoneal injections of T4 for 14 days. Although plasma Ang 1-7 levels were unchanged by hyperthyroidism, cardiac Ang 1-7 levels were increased in TH-induced cardiac hypertrophy. ACE2 enzymatic activity was significantly increased in hearts from hyperthyroid animals, which may be contributing to the higher Ang 1-7 levels observed in the T4 group. Furthermore, elevated cardiac levels of Ang 1-7 levels were accompanied by increased Mas receptor protein levels. The counter-regulatory components of the RAS are activated in hyperthyroidism and may be contributing to modulate the cardiac hypertrophy in response to TH.

Role of Oxidative Stress in Thyroid Hormone-Induced Cardiomyocyte Hypertrophy and Associated Cardiac Dysfunction: An Undisclosed Story.

Cardiac hypertrophy is the most documented cardiomyopathy following hyperthyroidism in experimental animals. Thyroid hormone-induced cardiac hypertrophy is described as a relative ventricular hypertrophy that encompasses the whole heart and is linked with contractile abnormalities in both right and left ventricles. The increase in oxidative stress that takes place in experimental hyperthyroidism proposes that reactive oxygen species are key players in the cardiomyopathy frequently reported in this endocrine disorder. The goal of this review is to shed light on the effects of thyroid hormones on the development of oxidative stress in the heart along with the subsequent cellular and molecular changes. In particular, we will review the role of thyroid hormone-induced oxidative stress in the development of cardiomyocyte hypertrophy and associated cardiac dysfunction, as well as the potential effectiveness of antioxidant treatments in attenuating these hyperthyroidism-induced abnormalities in experimental animal models.

Sexual dimorphism in autonomic changes and in the renin–angiotensin system in the hearts of mice subjected to thyroid hormone‐induced cardiac hypertrophy

Based on the relevance of the renin-angiotensin system and the ongoing controversy regarding the role of the sympathetic nervous system in thyroid hormone-induced cardiac hypertrophy, the aim of the present study was to establish whether the putative difference in the degree of cardiac hypertrophy exhibited by males and females might be related to differences in the sympathetic-vagal balance and/or in the cardiac renin-angiotensin system in mice of different genders. Male and female mice (n = 117) were given 0.1 mg kg(-1) of triiodothyronine or normal saline each day for 10 days consecutively. At the end of that period, study of the heart rate variability, spectral analysis and histopathological examination were performed to assess the sympathetic-vagal balance and the diameter of cardiomyocytes. The cardiac levels of angiotensin I and II were also measured. Treatment with triiodothyronine induced a greater degree of cardiac hypertrophy in male (~73%) than in female mice (~42%). This difference was attributed to greater modulation of the sympathetic nervous system and higher levels of angiotensin I and II in male than in female mice. Our data indicate that thyroid hormone-induced cardiac hypertrophy was more intense in male mice due to the synergic effect of the sympathetic nervous system and the cardiac renin-angiotensin system.

MiRNA-208a and miRNA-208b are triggered in thyroid hormone-induced cardiac hypertrophy – Role of type 1 Angiotensin II receptor (AT1R) on miRNA-208a/α-MHC modulation

Hyperthyroidism promotes cardiac hypertrophy and the Angiotensin type 1 receptor (AT1R) has been demonstrated to mediate part of this response. Recent studies have uncovered a potentially important role for the microRNAs (miRNAs) in the control of diverse aspects of cardiac function. Then, the objective of the present study was to investigate the action promoted by hyperthyroidism on β-MHC/miR-208b expression and on α-MHC/miR-208a expression, as well as the possible contribution of the AT1R in this event.The findings of this study confirmed that AT1R is a key mediator of the cardiac hypertrophy induced by hyperthyroidism. Additionally, we demonstrated that like β-MHC, miR-208b was down-regulated in the hyperthyroid group. Similarly, like the expression of its host gene, α-MHC, miR-208a expression was up-regulated in response to hyperthyroidism. Finally, our data suggest for the first time that AT1R mediates the hyperthyroidism-induced increase on cardiac miRNA-208a/α-MHC levels, while does not influence on the reduction of miRNA-208b/β-MHC levels.

Reactive oxygen and nitrogen species balance in the determination of thyroid hormones-induced cardiac hypertrophy mediated by renin–angiotensin system

Role of reactive oxygen species (ROS)/nitric oxide (NO) balance and renin–angiotensin system in mediating cardiac hypertrophy in hyperthyroidism was evaluated in an in vivo and in vitro experimental model. Male Wistar rats were divided into four groups: control, thyroid hormone, vitamin E (or Trolox, its hydrosoluble analogue), thyroid hormone + vitamin E. Angiotensin II receptor (AT1/AT2) gene expression, immunocontent of AT1/AT2 receptors, angiotensinogen, NADPH oxidase (Nox2), and nitric oxide synthase isoforms, as well as ROS concentration (hydrogen peroxide and superoxide anion) were quantified in myocardium. Thyroid hormone increased ROS and NO metabolites, iNOS, nNOS and eNOS isoforms and it was accompanied by cardiac hypertrophy. AT1/AT2 expression and the immunocontent of angiotensinogen and Nox2 were enhanced by thyroid hormone. Antioxidants reduced ROS levels, Nox2, AT1/AT2, NOS isoforms and cardiac hypertrophy. In conclusion, ROS/NO balance may play a role in the control of thyroid hormone-induced cardiac hypertrophy mediated by renin–angiotensin system.

Rapamycin Prevents Thyroid Hormone-Induced Cardiac Hypertrophy

Thyroid hormones (THs) have many effects on the cardiovascular system including cardiac hypertrophy. Although THs induce cardiac hypertrophy, the mechanism through which they exert this effect is unknown. We previously found that THs activate signaling related to increased protein synthesis [mammalian target of rapamycin (mTOR) and p70 S6 kinase] in the heart. It is unknown whether this activation contributes to TH-induced hypertrophy or whether it is merely incidental. In this study, we used rapamycin to inhibit mTOR function in mice and neonatal cardiomyocyte cultures treated with THs to test whether mTOR/S6 kinase signaling is involved in TH-mediated cardiac hypertrophy. C57 mice were treated with T4 for 3 d, 1 wk, 2 wk, or 1 month with either placebo, T4 (50 microg/100 g body weight.d), rapamycin (200 microg/100 g body weight.d) or T4/rapamycin by sc slow-release pellets. At the end of the treatment period, hemodynamics and physical data were collected and hearts were frozen for Western blot analysis or myocytes were isolated. The effects of T3 and rapamycin were also investigated using neonatal cardiomyocytes. THs activated specific components of the AKT signaling pathway in vivo and in vitro. THs induced cardiac hypertrophy, which was completely inhibited by rapamycin. Our results suggest that TH-induced hypertrophy is mediated by AKT/mTOR/S6 kinase signaling, which is important in the regulation of protein synthesis, a hallmark of cardiac hypertrophy.

Angiotensin type 1 (AT1) and type 2 (AT2) receptors mediate the increase in TGF-β1 in thyroid hormone-induced cardiac hypertrophy

Increased thyroid hormone (TH) levels are known to induce cardiac hypertrophy. Some studies have provided evidence for a functional link between angiotensin II (ANG II) and transforming growth factor beta1 (TGF-beta1) in the heart, both being able to also induce cardiac hypertrophy. However, the contribution of this growth factor activated directly by TH or indirectly by ANG II in cardiac hypertrophy development remains unknown. To analyze the possible role of TGF-beta1 in cardiac hypertrophy induced by TH and also to evaluate if the TGF-beta1 effect is mediated by ANG II receptors, we employed Wistar rats separated into control, hypothyroid (hypo) and hyperthyroid (T4 - 10) groups combined or not with ANG II receptor blockers (losartan or PD123319). Serum levels of T3 and T4, systolic pressure and heart rate confirmed the thyroid state of the groups. The T4 - 10 group presented a significant increase in cardiac TGF-beta1 levels; however, TGF-beta1 levels in the hypo group did not change in relation to the control. Inhibition of the increase in cardiac TGF-beta1 levels was observed in the groups treated with T4 in association with losartan or PD123319 when compared to the T4 - 10 group. These results demonstrate for the first time the TH-modulated induction of cardiac TGF-beta1 in cardiac hypertrophy, and that this effect is mediated by ANG II receptors.

Effects of triiodo-thyronine on angiotensin-induced cardiomyocyte hypertrophy: reversal of increased β-myosin heavy chain gene expression

Thyroid hormone-induced cardiac hypertrophy is similar to that observed in physiological hypertrophy, which is associated with high cardiac contractility and increased alpha-myosin heavy chain (alpha-MHC, the high ATPase activity isoform) expression. In contrast, angiotensin II (Ang II) induces an increase in myocardial mass with a compromised contractility accompanied by a shift from alpha-MHC to the fetal isoform beta-MHC (the low ATPase activity isoform), which is considered as a pathological hypertrophy and inevitably leads to the development of heart failure. The present study is designed to assess the effect of thyroid hormone on angiotensin II-induced hypertrophic growth of cardiomyocytes in vitro. Cardiomyocytes were prepared from hearts of neonatal Wistar rats. The effects of Ang II and 3,3',5-triiodo-thyronine (T3) on incorporations of [3H]-thymine and [3H]-leucine, MHC isoform mRNA expression, PKC activity, and PKC isoform protein expression were studied. Ang II enhanced [3H]-leucine incorporation, beta-MHC mRNA expression, PKC activity, and PKCepsilon expression and inhibited alpha-MHC mRNA expression in cardiomyocytes. T3 treatment prevented Ang II-induced increases in PKC activity, PKCepsilon, and beta-MHC mRNA overexpression and favored alpha-MHC mRNA expression. Thyroid hormone appears to be able to reprogram gene expression in Ang II-induced cardiac hypertrophy, and a PKC signal pathway may be involved in such remodeling process.

Decreased protein kinase C-epsilon expression in hypertrophied cardiac ventricles induced by triiodothyronine treatment in the rat

To examine the effect of thyroid hormone-induced cardiac hypertrophy on PKC expression, changes in the expression of PKC isoforms were studied in hypertrophied cardiac ventricles induced by triiodothyronine (T3) injection in the rat. Injection with T3 for 8 days induced 49% increase in cardiac weight compared to controls. Immunoblot analysis of cardiac ventricular extracts showed the expression of PKC-δ, -ε, and -ζ in both control and T3-treated groups. The expression of PKC-ε decreased by 40% in hyperthyroid rat cardiac ventricles, while PKC-δ and -ζ expressions were barely affected. PKC-ε immunoreactivity decreased in both cytosol and membrane fractions. On the contrary, PKC-ε expression did not decrease in the extract of hypertrophied cardiac ventricles produced by aortic banding or aortocaval shunt. These results indicate that thyroid hormone down regulates PKC-ε expression in the hyperthyroid-mediated cardiac hypertrophy.

Thyroid hormone-induced overexpression of functional ryanodine receptors in the rabbit heart.

Modifications in the Ca(2+)-uptake and -release functions of the sarcoplasmic reticulum (SR) may be a major component of the mechanisms underlying thyroid state-dependent alterations in heart rate, myocardial contractility, and metabolism. We investigated the influence of hyperthyroid state on the expression and functional properties of the ryanodine receptor (RyR), a major protein in the junctional SR (JSR), which mediates Ca(2+) release to trigger muscle contraction. Experiments were performed using homogenates and JSR vesicles derived from ventricular myocardium of euthyroid and hyperthyroid rabbits. Hyperthyroidism, with attendant cardiac hypertrophy, was induced by the injection of L-thyroxine (200 microg/kg body wt) daily for 7 days. Western blotting analysis using cardiac RyR-specific antibody revealed a significant increase (>50%) in the relative amount of RyR in the hyperthyroid compared with euthyroid rabbits. Ca(2+)-dependent, high-affinity [(3)H]ryanodine binding was also significantly greater ( approximately 40%) in JSR from hyperthyroid rabbits. The Ca(2+ )sensitivity of [(3)H]ryanodine binding and the dissociation constant for [(3)H]ryanodine did not differ significantly between euthyroid and hyperthyroid hearts. Measurement of Ca(2+)-release rates from passively Ca(2+)-preloaded JSR vesicles and assessment of the effect of RyR-Ca(2+)-release channel (CRC) blockade on active Ca(2+)-uptake rates revealed significantly enhanced (>2-fold) CRC activity in the hyperthyroid, compared with euthyroid, JSR. These results demonstrate overexpression of functional RyR in thyroid hormone-induced cardiac hypertrophy. Relative abundance of RyR may be responsible, in part, for the changes in SR Ca(2+) release, cytosolic Ca(2+) transient, and cardiac systolic function associated with thyroid hormone-induced cardiac hypertrophy.

Coordinated capillary and myocardial growth in response to thyroxine treatment.

Thyroid hormone-induced cardiac hypertrophy is a model of enhanced physiological growth and angiogenesis. This study addressed the growth and geometry of the capillary bed in relation to the development of cardiac hypertrophy. Thyroxine was administered daily (0.2 mg/kg, s.c.) for 5 or 10 days to Fischer 344 rats. After obtaining ventricular function and hemodynamic data, the hearts were perfuse fixed, and specimens from the left ventricle (LV) were subjected to image analysis to determine indices of capillary growth. After 5 days of treatment, prior to cardiac enlargement, capillary length density was significantly greater in the epimyocardium of the thyroxine rats than in the controls (saline injected). Most of the increase could be attributed to an increase in capillary numerical density, but some enhancement in capillary profile axial ratio suggests that enhanced tortuosity or formation of oblique channels also occurred. After 10 days of treatment, all capillary parameters (length, volume, and surface densities) were similar to the controls despite a 30% enlargement of the LV. We estimate that total LV capillary length increased by 14% during the first 5 days and by 9% during the next 5 days of treatment. These findings indicate that capillary angiogenesis precedes the development of ventricular enlargement due to thyroxine administration. Therefore, angiogenesis in this model is not stimulated by the presence of hypertrophy.

Coordinated capillary and myocardial growth in response to thyroxine treatment

Background Thyroid hormone-induced cardiac hypertrophy is a model of enhanced physiological growth and angiogenesis. This study addressed the growth and geometry of the capillary bed in relation to the development of cardiac hypertrophy. Methods Thyroxine was administered daily (0.2 mg/kg, s.c.) for 5 or 10 days to Fischer 344 rats. After obtaining ventricular function and hemodynamic data, the hearts were perfuse fixed, and specimens from the left ventricle (LV) were subjected to image analysis to determine indices of capillary growth. Results After 5 days of treatment, prior to cardiac enlargement, capillary length density was significantly greater in the epimyocardium of the thyroxine rats than in the controls (saline injected). Most of the increase could be attributed to an increase in capillary numerical density, but some enhancement in capillary profile axial ratio suggests that enhanced tortuosity or formation of oblique channels also occurred. After 10 days of treatment, all capillary parameters (length, volume, and surface densities) were similar to the controls despite a 30% enlargement of the LV. We estimate that total LV capillary length increased by 14% during the first 5 days and by 9% during the next 5 days of treatment. Conclusions These findings indicate that capillary angiogenesis precedes the development of ventricular enlargement due to thyroxine administration. Therefore, angiogenesis in this model is not stimulated by the presence of hypertrophy. Anat. Rec. 251:44–49, 1998. © 1998 Wiley-Liss, Inc.

Molecular and cellular mechanisms of induction and regression of cardiac fibrosis in various models of myocardial hypertrophy

This review is the summary of our findings on collagen gene expression and regulation in ventricular myocardium in experimental animal models of cardiac hypertrophy and in cardiac fibroblasts in response to hormonal stimuli. Cardiac fibrosis, or accumulation of collagen in the myocardium, is seen in several models of cardiac hypertrophy, such as those induced by aging, pressure overload, and norepinephrine-induced hypertension. Results on collagen gene expression have indicated that initial up-regulation of collagen gene expression usually precedes collagen accumulation in hypertrophied heart in those models. Thyroid hormone-induced cardiac hypertrophy, however, is distinguished from those types of hypertrophy by the absence of fibrosis and by down-regulation of collagen gene expression in ventricular tissue. Our in vitro studies on cardiac fibroblasts indicate that absence of fibrosis in thyroid hormone-induced hypertrophy could be the result of an inhibitory effect of thyroid hormone on collagen gene expression at transcriptional levels. Thyroid hormone was also shown to cause regression of cardiac fibrosis in the heart of a genetic model of collagen overproduction, the tight skin (TSK) mouse. These findings indicate that cardiac fibrosis and cardiac hypertrophy are induced via different mechanisms and that presence of cardiac hypertrophy does not imply cardiac fibrosis. The findings on inhibitory effects of thyroid hormone on collagen gene expression further suggest that biological inhibitory pathways, such as hormonal regulation, could be activated to compensate for excessive collagen production or for diminished collagen degradation by cardiac fibroblasts in cases of predisposition to cardiac fibrosis.

Thyroxine-induced cardiac hypertrophy: time course of development and inhibition by propranolol.

To investigate the mechanism of thyroid hormone-induced cardiac hypertrophy, we have studied the in vivo changes in cardiac size and total myocardial content of both membrane and cytoskeletal enzymes in the rat after the administration of excess thyroid hormone. In response to 50 micrograms T4/day, there is a significant increase in heart rate and heart work associated with an increase in total heart size and protein content. Measurements of the specific activity of Na,K-ATPase and p-nitrophenol phosphatase demonstrate a small but significant increase in specific activity, while the specific activity of myosin ATPase is unchanged. To further probe the mechanism for T4-mediated hypertrophy we studied the in vivo effects of beta-adrenergic blockade on rat heart size. When animals were treated with both T4 and propranolol (10 mg/animal.day) cardiac hypertrophy was prevented. Propranolol alone at this dose did not affect heart rate, heart weight, or serum levels of T4 and T3. The present data suggest that 1) the hypertrophic response of the myocardium to excess thyroid hormone involves cytoplasmic as well as membrane proteins, 2) the increase in total myocardial protein, which can be blocked by propranolol, is indirectly mediated by increases in cardiac work rather than a direct effect of thyroid hormone.

Effects of thyroid hormone on cardiac size and myosin content of the heterotopically transplanted rat heart.

Infrarenal heterotopic cardiac isografts maintain structural and functional integrity. We have used this transplantation model to further explore the mechanisms of thyroid hormone-induced cardiac hypertrophy. Thyroid hormone administration, 1-thyroxine (T4) 10 micrograms/animal per d, led to a significant 30% increase in total heart weight and a 40% increase in the myosin content of the in situ heart when compared with control. In contrast, T4 treatment was without effect on the heart weight, protein content, rate of protein synthesis, or calculated myosin content of the heterotopic, nonworking heart. Heterotopic hearts demonstrated a significant decrease in the percentage of the V1 myosin isoenzyme from 95% to 61%. This shift occurred in euthyroid animals but was prevented by T4 treatment. These results suggest that thyroxine-induced cardiac hypertrophy is mediated indirectly via changes in cardiac work. Myosin isoenzyme expression can be altered by changes in work load but is still responsive to increased levels of thyroid hormone.