RESUMEN
BACKGROUND AND OBJECTIVE: All three isoforms of nitric oxide (NO) synthase (NOS) are targets for thyroid hormones in the cardiovascular system. The aim of this study was to assess the effects of hypo- and hyperthyroidism on inducible (iNOS), endothelial (eNOS), and neural (nNOS) NOS levels in aorta and heart tissues of male rats. METHODS: Rats were divided into control, hypothyroid, and hyperthyroid groups; hypo- and hyperthyroidism were induced by adding propylthiouracil (500 mg/L) and L-thyroxine (12 mg/L) to drinking water for a period of 21 days. On day 21, systolic blood pressure, heart rate, left ventricular developed pressure (LVDP), peak rate of positive and negative (±dp/dt) changes in left ventricular pressure as well as NO metabolites (NOx) and iNOS, eNOS, and nNOS protein levels in aorta and heart, were all measured. RESULTS: Compared to controls, LVDP and ±dp/dt were lower in both hypo- and hyperthyroid rats. Compared to controls, heart rate and systolic blood pressure were lower in hypothyroid and higher in hyperthyroid rats. NOx levels in the heart of hypothyroid rats were lower (53%), whereas that in hyperthyroid rats were higher (56% and 40%) than controls. Compared to controls, hypothyroid rats had lower levels of eNOS, iNOS, and nNOS in the aorta (16%, 34%, and 15%, respectively) and lower iNOS and higher nNOS in heart tissue (27% and 46%). In hyperthyroid rats, eNOS levels were lower (54% and 30%) and iNOS were higher (63%, and 35%) in the aorta and heart while nNOS was lower in the aorta (18%). CONCLUSION: Hypothyroidism increased while hyperthyroidism decreased the ratio of eNOS/iNOS in aorta and heart; these changes of NOS levels were associated with impaired cardiovascular function.
Asunto(s)
Sistema Cardiovascular/enzimología , Hipertiroidismo/enzimología , Hipotiroidismo/enzimología , Óxido Nítrico Sintasa/metabolismo , Animales , Sistema Cardiovascular/fisiopatología , Modelos Animales de Enfermedad , Hemodinámica , Hipertiroidismo/sangre , Hipertiroidismo/fisiopatología , Hipotiroidismo/sangre , Hipotiroidismo/fisiopatología , Masculino , Óxido Nítrico Sintasa de Tipo I/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ratas Wistar , Hormonas Tiroideas/sangre , Función Ventricular IzquierdaRESUMEN
OBJECTIVES: Although a single nucleotide polymorphism in a specific receptor for lysophosphatidylserine, a lysophospholipid mediator involved in the immune system, is reportedly associated with Graves' disease, the association between lysophosphatidylserine and thyroid disorders remains to be elucidated. Therefore, we aimed to investigate the association between the level of phosphatidylserine-specific phospholipase A1 (PS-PLA1), which produces lysophosphatidylserine, and thyroid disorders. METHODS: We measured serum PS-PLA1 levels in the patients with various thyroid disorders (n = 120) and normal subjects (n = 58). RESULTS: We observed that the serum PS-PLA1 levels were higher in the subjects with Graves' disease, subacute thyroiditis, or silent thyroiditis, while they were not modulated in the patients with hypothyroidism. The serum PS-PLA1 levels were strongly correlated with the levels of thyroid hormones, especially in the subjects with Graves' disease. Moreover, we found that the serum PS-PLA1 levels were lowered by treatment with anti-thyroid reagents in subjects with Graves' disease and that the changes in PS-PLA1 were strongly correlated with those in thyroid hormones. CONCLUSION: These results suggest that PS-PLA1 might be a novel target in the treatment of hyperthyroidism, especially Graves' disease, and that its measurement might be useful as a supplementary diagnostic test for thyroid function.
Asunto(s)
Hipertiroidismo/enzimología , Fosfolipasas A1/sangre , Adulto , Estudios de Casos y Controles , Femenino , Enfermedad de Graves/sangre , Humanos , Hipertiroidismo/sangre , Lisofosfolípidos , Masculino , Persona de Mediana Edad , FosfatidilserinasRESUMEN
Thyroid hormones (THs) are vital for normal reproductive function and dysregulation of TH impairs follicular development. Although the functions of THs on female reproduction are of great interest, the mechanisms still remain unclear. Many studies have shown that NO plays important roles in female reproduction. In the present study, we investigate the effects of TH dysregulation on nitric oxide synthase types (NOS) expression in rats. Propylthiouracil (PTU) and L-thyroxine were administered to rats to induce hypo- and hyperthyroidism, respectively. Ovarian histology was detected by immunohistochemistry (IHC) and protein or mRNA content was analyzed by Western blotting or RT-PCR, respectively. The results showed that NOS1, NOS2 and NOS3 expressions were detected in the oocyte, granulosa cell and theca cell in all follicular stages, which were up-regulated by eCG treatment. NOS1 protein content was increased in both PTU and L-thyroxine treatments. There were no significant differences in NOS2 levels between the treatment and the control group. However, NOS3 was only increased in the hyperthyroid group. These results were consistent with the IHC staining. The present study provides evidence that TH dysregulation alters NOSs profiles, which suggests that NOSs/nitric oxide (NO) is possibly involved in the regulation of female reproduction.
Asunto(s)
Óxido Nítrico Sintasa/metabolismo , Glándula Tiroides/enzimología , Glándula Tiroides/fisiopatología , Animales , Gonadotropina Coriónica/farmacología , Femenino , Caballos , Hipertiroidismo/enzimología , Hipotiroidismo/enzimología , Isoenzimas/metabolismo , Folículo Ovárico/efectos de los fármacos , Folículo Ovárico/enzimología , Ratas Sprague-Dawley , Glándula Tiroides/efectos de los fármacos , Hormonas Tiroideas/metabolismoRESUMEN
Hyperthyroidism is an endocrine disorder characterized by excessive secretion of thyroid hormones T3 and T4. Thyroid hormones exert pleiotropic actions on numerous tissues and induce an overall increase in metabolism, with an increase in energy demand and oxygen consumption. Therefore, the purpose of this study was to investigate the effects of hyperthyroidism on the production of reactive oxygen species (ROS) in lymph node and spleen cells of euthyroid and hyperthyroid mice, analyzing antioxidant mechanisms involved in the restitution of the cellular redox state. For this, thirty female Balb/c (H-2d) mice were randomly divided into two groups: euthyroid (by treatment with placebo) and hyperthyroid (by treatment with 12 mg/l of T4 in drinking water for 30 days). We found a significant increase in ROS and an increase in the genomic and protein expression of the antioxidant enzymes catalase (CAT) and glutathione peroxidase-1 (GPx-1) in lymph node and spleen cells of hyperthyroid mice. In vitro treatment with H2O2 (250 µM) of the lymphoid cells of euthyroid mice increased the expression levels of CAT and GPx-1. The hyperthyroidism increased the phosphorylation levels of Nrf2 (nuclear factor erythroid 2-related factor) and the kinase activity of protein kinase C (PKC) and extracellular signal-regulated kinase (ERK). Additionally, we found an increase in the expression of the classic isoenzymes of PKCα, ß and γ. In conclusion, these results indicated that the increase in ROS found in the hyperthyroid state induces the antioxidant enzyme transcription through the activation of the Nrf-2 factor in lymphoid tissues. This shows the influence of hyperthyroidism on the regulation of the cellular antioxidant system.
Asunto(s)
Catalasa/genética , Glutatión Peroxidasa/genética , Hipertiroidismo/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/fisiología , Superóxido Dismutasa-1/genética , Animales , Catalasa/biosíntesis , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Glutatión Peroxidasa/biosíntesis , Hipertiroidismo/sangre , Hipertiroidismo/enzimología , Hipertiroidismo/genética , Tejido Linfoide/metabolismo , Ratones , Ratones Endogámicos BALB C , Factor 2 Relacionado con NF-E2/genética , Proteína Quinasa C/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa-1/biosíntesis , Tirotropina/sangre , Tiroxina/administración & dosificación , Tiroxina/sangre , Activación Transcripcional , Triyodotironina/sangre , Glutatión Peroxidasa GPX1RESUMEN
Thyroid hormones have a role in the regulation of hydrogen sulfide (H2 S) biosynthesis. In this study, we determined the effects of hyperthyroidism on H2 S levels in various tissues and messenger RNA (mRNA) expression of cystathionine-ß-synthase (CBS), cystathionine-γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST) in the liver and muscles of the rat. Sixteen male Wistar rats were divided into the hyperthyroid and the control groups. Hyperthyroidism was induced by adding l-thyroxine (12 mg/L) to drinking water for a period of 21 days. H2 S concentrations in serum, liver, aorta, heart, and soleus muscles, as well as mRNA expressions of CBS, CSE, and 3-MST in these tissues were measured at Day 21. Hyperthyroid rats had lower H2 S levels in the serum compared with controls (14.7 ± 1.4 vs. 25.7 ± 1.6 µmol/L, p < 0.001). Compared with controls, hyperthyroid rats had lower levels of H2 S in the aorta (89%), heart (80%), and soleus (103%) muscles, but higher levels in the liver (35%). Hyperthyroidism decreased the ratio of CBS/CSE mRNA expression in the liver and the CSE/CBS mRNA expression in the muscles by decreasing CBS levels in liver (34% cf. controls) and CSE levels in the aorta, heart, and soleus muscles (respectively, 51%, 7%, and 52% cf.). In addition, hyperthyroidism decreased the mRNA expression of 3-MST in the liver (51%) and aorta (33%), and increased it in the heart (300%) and soleus muscle (182%). In conclusion, hyperthyroidism increased H2 S levels in the liver and decreased it in muscles; these effects are at least in part due to increases and decreases in expression of CSE in the liver and muscles, respectively. These data indicate an association between thyroid hormone status and gene expression of the H2 S-producing enzymes in the rat.
Asunto(s)
Cistationina betasintasa/metabolismo , Cistationina gamma-Liasa/metabolismo , Sulfuro de Hidrógeno/metabolismo , Hipertiroidismo/enzimología , Hígado/enzimología , Músculo Esquelético/enzimología , Músculo Liso Vascular/enzimología , Miocardio/enzimología , Sulfurtransferasas/metabolismo , Animales , Cistationina betasintasa/genética , Cistationina gamma-Liasa/genética , Modelos Animales de Enfermedad , Regulación hacia Abajo , Regulación Enzimológica de la Expresión Génica , Sulfuro de Hidrógeno/sangre , Hipertiroidismo/sangre , Hipertiroidismo/genética , Masculino , Ratas Wistar , Sulfurtransferasas/genéticaRESUMEN
The Neuropeptide EI (NEI, glutamic acid- isoleucine amide) participates in neuroendocrine function. Previously we demonstrated that NEI concentration is regulated by thyroid hormones in discrete hypothalamic areas in rats. We observed that the thyroid status affects the dopaminergic regulation of the pituitary hormones. In this study we explored possible interactions between NEI and tyrosine hydroxylase (TH) containing elements in selected hypothalamic areas of male rats. Neuronal somas, terminals and boutons were assessed by confocal microscopy, in hypo- and hyperthyroid animals. We observed a remodeling of the contacts between the TH and NEI immunoreactive elements in the incerto-hypothalamic area (IHy, also known as rostromedial zona incerta) according to thyroid function. However, in the dorsolateral zone of the peduncular part of the lateral hypothalamus (DL-PLH) the thyroid hormones affect the dendritic trees of the neurons without perturbing the overall NEI/TH contacts. Also, we demonstrated that TRH Receptor 1 (TRH-R1) is colocalized in NEI immunoreactive neurons in the peduncular part of the lateral hypothalamus (PLH) and NEI precursor mRNA expression increased by hypothyroidism indicating that NEI neurons are responsive to the feedback mechanisms of the Hypothalamic Pituitary-Thyroid Axis (HPT). In conclusion, the hypothyroid status seems to increase the interactions between the NEI neurons and the dopaminergic pathways while hyperthyroidism either decreases or displays no effects. Altogether these observations support the participation of the IHy and PLH NEI as a modulating component of the HPT suggesting that altered neuroendocrine, behavioral and cognitive dysfunctions induced by dysthyroidism could be in part mediated by NEI.
Asunto(s)
Hipertiroidismo/metabolismo , Hipotálamo/metabolismo , Hipotiroidismo/metabolismo , Plasticidad Neuronal , Oligopéptidos , Tirosina 3-Monooxigenasa , Animales , Hipertiroidismo/enzimología , Hipertiroidismo/fisiopatología , Hipotálamo/enzimología , Hipotálamo/fisiopatología , Hipotiroidismo/enzimología , Hipotiroidismo/fisiopatología , Masculino , Neuronas/enzimología , Neuronas/metabolismo , Neuronas/fisiología , Ratas , Ratas WistarRESUMEN
The purinergic system has an important role in the regulation of vascular functions. The interference of thyroid hormones in this system and in cardiovascular events has been studied in recent years. However, the mechanisms involved in vascular, purinergic, and oxidative changes in thyroid disorders are not completely understood. Therefore, the present study aimed to assess purinergic enzyme activity in platelets from rats with hypothyroidism and hyperthyroidism induced, respectively, by continuous exposure to methimazole (MMI) at 20 mg/100 mL or L-thyroxine at 1.2 mg/100 mL in drinking water for 1 month. Results showed that rats exposed to L-thyroxine had a significant decrease in NTPDase activity, wherein ATP hydrolysis was 53% lower and ADP hydrolysis was 40% lower. Moreover, ecto-5'-nucleotidase activity was decreased in both groups, by 39% in the hypothyroidism group and by 52% in the hyperthyroidism group. On the other hand, adenosine deaminase (ADA) activity was increased in hyperthyroidism (75%), and nucleotide pyrophosphatase/phosphodiesterase (NPP) activity was increased in animals with hypothyroidism (127%) and those with hyperthyroidism (128%). Our findings suggest that changes in purinergic enzyme and purine levels could contribute to the undesirable effects of thyroid disturbances. Moreover, oxidative stress and, in particular, a high level of ROS production, showed a causal relation with changes in ectonucleotidase activity and nucleotide and nucleoside levels.
Asunto(s)
5'-Nucleotidasa/metabolismo , Adenosina Desaminasa/metabolismo , Antígenos CD/metabolismo , Apirasa/metabolismo , Plaquetas/enzimología , Hipertiroidismo/enzimología , Hipotiroidismo/enzimología , Nucleótidos/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Hidrólisis , Hipertiroidismo/sangre , Hipertiroidismo/inducido químicamente , Hipotiroidismo/sangre , Hipotiroidismo/inducido químicamente , Masculino , Metimazol/toxicidad , Estrés Oxidativo , Ratas , Ratas WistarRESUMEN
Graves' ophthalmopathy is characterized by hyperthyroidism, which is associated with higher serum T3 levels than T4 due to deiodinase enzymes.The effect of Graves' patient's sera (n=52) with elevated thyroid hormone and TSH receptor or thyroid peroxidase antibody (anti-TPO) levels was investigated on thyroidal, skeletal and eye muscle type 2 deiodinase enzyme (DII) activities. DII activities were measured with 125I-T4 substrate, while thyroid hormone and antibody levels with immunoassays.In Graves' ophthalmopathy, sera with elevated FT4 or FT3 levels reduced DII activites remarkably in all tissue fractions. Thyroidal DII activities were lower than those using eye muscle fraction (0.6±0.22 vs 1.14±0.43 pmol/mg/min, P<0.006). Effect of sera with increased FT3 levels demonstrated also reduced DII activities in patients with Graves' ophthalmopathy after methimazole therapy compared to those who had no ophthalmopathy (2.88±2 vs 20.42±11.82 pmol/mg/min, P<0.006 for thyroidal fraction, 4.07±2.72 vs 29.22±15.46 pmol/mg/min, P<0.004 for skeletal muscle, 5.3±3.47 vs 37.87±18.82 pmol/mg/min, P<0.003 for eye muscle). Hyperthyroid sera with TSH receptor antibodies resulted in increased DII activities, while sera with anti-TPO antibodies were connected to lower DII activities in Graves' ophthalmopathy.In summary, the actions of hyperthyroid sera derived from patients with Graves' disease were tested on tissue-specific DII activities. Elevated FT4 level-induced DII inactivation is present in Graves' ophthalmopathy, which seems to be also present at the beginning of methimazole therapy. Stimulating TSH receptor antibiodies increased DII activities via their nongenomic effects using sera of hyperthyroid Graves' ophthalmopathy, but anti-TPO antibodies could influence DII activities via altering FT4 levels.
Asunto(s)
Oftalmopatía de Graves/enzimología , Hipertiroidismo/enzimología , Yoduro Peroxidasa/metabolismo , Músculo Esquelético/enzimología , Glándula Tiroides/enzimología , Adulto , Femenino , Oftalmopatía de Graves/patología , Humanos , Hipertiroidismo/patología , Masculino , Persona de Mediana Edad , Glándula Tiroides/patología , Tiroxina/sangre , Triyodotironina/sangre , Yodotironina Deyodinasa Tipo IIRESUMEN
OBJECTIVE: To investigate the underlying mechanisms of cyclovirobuxinum D (Cvb-D) on alleviating cardiac hypertrophy in rats. METHODS: Sprague-Dawley rats were randomly divided into 5 groups: control group; levothyroxine-induced cardiac hypertrophy group (model); levothyroxine-induced cardiac hypertrophy + Cvb-D group (Cvb-D); levothyroxine-induced cardiac hypertrophy + captopril group (captopril); levothyroxine-induced cardiac hypertrophy + SB203580 group (SB203580), n=10 for each group. Rats were daily administered the respective drugs continuously for14 days by gastric gavage. A rat model of cardiac hypertrophy was established by intraperitoneal injection of levothyroxine to investigate whether Cvb-D protects against cardiac hypertrophy by inhibiting the p38 mitogen-activated protein kinase (MAPK) signaling pathway and preventing apoptosis of cardiac cells. RESULTS: Treatment with Cvb-D significantly deceased left ventricle hypertrophy, improved the histopathology, hemodynamic conditions, and cardiac function in rats with cardiac hypertrophy. Compared with the normal control group, in rats with cardiac hypertrophy, expression of bax in the heart and phospho-p38 MAPK protein levels were significantly up-regulated (P<0.01 or 0.05), whereas the bcl-2 protein level was down-regulated (P<0.01). In contrast, Cvb-D treatment reversed the changes in bax and phospho-p38 MAPK protein levels but increased the bcl-2 protein level (P<0.01 or 0.05), and these effects were similar to those of captopril and SB203580 (a specific p38MAPK inhibitor) treatment. Furthermore, both Cvb-D, captopril and SB203580 reduced mRNA expression of p38α, p38ß, c-fos, and c-jun mRNA, and Cvb-D had a stronger effect (P<0.01). CONCLUSION: These results demonstrate that Cvb-D protects against cardiac hypertrophy, which is possibly mediated by prevention of cardiac cell apoptosis and inhibition of the p38MAPK signaling pathway.
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Apoptosis , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/patología , Medicamentos Herbarios Chinos/uso terapéutico , Hipertiroidismo/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas , Miocitos Cardíacos/patología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Apoptosis/efectos de los fármacos , Cardiomegalia/complicaciones , Cardiomegalia/enzimología , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Ácidos Grasos/metabolismo , Hemodinámica/efectos de los fármacos , Hipertiroidismo/complicaciones , Hipertiroidismo/enzimología , Hipertiroidismo/patología , Hipertrofia Ventricular Izquierda/complicaciones , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/patología , Riñón/efectos de los fármacos , Riñón/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Malondialdehído/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Fosforilación/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Superóxido Dismutasa/metabolismoRESUMEN
Iodotyrosine deiodinase (DEHAL1) is a crucial enzyme in iodine homeostasis. Unbound mono- and diiodotyrosines are indispensable byproducts of thyroid hormone biosynthesis. Their iodine needs to be recovered to avoid iodine deficiency, as observed in genetic defects in DEHAL1. Despite its importance, the enzyme is rarely studied. The deiodination process can be monitored by radioactive tracers or via techniques involving mass spectrometry. However, isotope-labeled molecules are expensive, not always commercially available, and their use is legally restricted, whereas mass spectrometry requires sophisticated, costly, and sensitive instrumentation. To circumvent these difficulties, we adapted the nonradioactive iodothyronine deiodinase assay to determine DEHAL1 activity by a colorimetric readout, based on the Sandell-Kolthoff reaction. DEHAL1 was recombinantly expressed and used to optimize the assay in microtiter format. We applied the setup to scenarios of alternative substrate screening or search for compounds potentially acting as endocrine disrupting compounds, without identifying novel readily accepted substrates or inhibitors yet. Next, the assay was adapted to ex vivo material, and activity was reliably determined from rodent kidney and other tissues. Analyzing two mouse models of hyperthyroidism, we observed a decreased renal Dehal1 activity and mRNA expression. Our results show that this nonradioactive DEHAL1 assay is suited to screen for potential endocrine disrupters and to monitor endogenous Dehal1 expression. We harmonized the assay protocols to enable iodothyronine deiodinase and DEHAL1 activity measurements from the same samples. Hereby, a more complete view on iodine metabolism by these predominant deiodinating activities can be obtained from a given sample by a similar process flow.
Asunto(s)
Hipertiroidismo/enzimología , Yoduro Peroxidasa/análisis , Tirotoxicosis/enzimología , Animales , Colorimetría , Masculino , RatonesRESUMEN
Ischemic postconditioning (IPost) is a strategy to provide protection against ischemia-reperfusion (IR) injury. The cardioprotective effects of IPost in cases of ischemic heart disease along with co-morbidities like hyperthyroidism remain unknown. The aim of this study was to investigate the effects of IPost on expression of eNOS, iNOS, Bax, and Bcl-2 genes in hyperthyroid male rats, subjected to myocardial IR. Hyperthyroidism was induced by adding thyroxine to drinking water for a period of 21 days. Using the Langendorff device hearts were perfused, then subjected to a 30-minute global ischemia which was followed by 120 min of reperfusion; subsequently IPost was induced immediately after ischemia. Results indicated that following IR, expression of eNOS and Bcl-2 decreased, whereas expression of iNOS and Bax increased in both the control and hyperthyroid groups. In hyperthyroid animals, IPost significantly increased expression of eNOS by 3.19 fold and Bcl-2 by 3.66 fold; it also decreased expression of Bax by 51%, and reduced IR-induced DNA laddering pattern and infarct size (45.7 ± 1.82% vs. 59.3 ± 1.83%, p<0.05) in the presence of aminoguanidine (AG), a selective iNOS inhibitor. In conclusion, IPost per se could not provide cardioprotection against myocardial ischemia in hyperthyroid rats, a loss of which however was restored by the combination of IPost and iNOS inhibition that acts by a decrease in Bax and an increase in both eNOS and Bcl-2 expression.
Asunto(s)
Apoptosis , Hipertiroidismo/enzimología , Poscondicionamiento Isquémico , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Daño por Reperfusión/prevención & control , Animales , Hipertiroidismo/patología , Masculino , Ratas , Ratas WistarRESUMEN
OBJECTIVE: Thyroid disorders may affect blood pressure and renal function modifying factors of the plasmatic and kidney renin-angiotensin system such as aminopeptidase A (AP A) that metabolizes angiotensin II to angiotensin III. We investigated the expression of AP A in the kidney, as well as its enzymatic activity in the plasma of euthyroid, hyperthyroid, and hypothyroid adult male rats. METHODS: Hyperthyroidism was induced by daily subcutaneous injections of tetraiodothyronine. Hypothyroid rats were obtained by administration of methimazole in drinking water. Expression of AP A was determined by Western blot analysis. Plasma AP A activity was measured fluorometrically using glutamyl-ß-naphthylamide as substrate. RESULTS: While hyperthyroid rats exhibited lower levels of plasma AP A activity than controls, the kidney of hyperthyroid animals expressed significantly higher AP A than controls and hypothyroid animals. CONCLUSIONS: A discrepancy between the high expression of AP A in kidney of hyperthyroid rats and the low activity of AP A measured in plasma and kidney of hyperthyroid animals was found. The posttranslational influence of environmental biochemical factors may be in part responsible for that divergence.
Asunto(s)
Glutamil Aminopeptidasa/metabolismo , Bocio Nodular/enzimología , Hipertiroidismo/enzimología , Hipotiroidismo/enzimología , Riñón/enzimología , Animales , Modelos Animales de Enfermedad , Activación Enzimática , Glutamil Aminopeptidasa/sangre , Bocio Nodular/sangre , Hipertiroidismo/sangre , Hipotiroidismo/sangre , Masculino , Ratas , Ratas WistarRESUMEN
BACKGROUND: Thyroid hormones (THs) are key regulators of cardiac physiology as well as modulators of different cellular signals including the sphingomyelin/ceramide pathway. The objective of this study was to examine the effect of hyperthyroidism on the metabolism of sphingolipids in the muscle heart. METHODS: Male Wistar rats were treated for 10 days with triiodothyronine (T3) at a dose of 50µg/100g of body weight. Animals were then anaesthetized and samples of the left ventricle were excised. RESULTS: We have demonstrated that prolonged, in vivo, T3 treatment increased the content of sphinganine (SFA), sphingosine (SFO), ceramide (CER) and sphingomyelin (SM), but decreased the level of sphingosine-1-phosphate (S1P) in cardiac muscle. Accordingly, the changes in sphingolipids content were accompanied by a lesser activity of neutral sphingomyelinase and without significant changes in ceramidases activity. Hyperthyroidism also induced activation of AMP-activated protein kinase (AMPK) with subsequently increased expression of mitochondrial proteins: cytochrome c oxidase IV (COX IV), ß-hydroxyacyl-CoA dehydrogenase (ß-HAD), carnityne palmitoyltransferase I (CPT I) and nuclear peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α). CONCLUSIONS: We conclude that prolonged T3 treatment increases sphingolipids metabolism which is reflected by higher concentration of SFA and CER in heart muscle. Furthermore, hyperthyroidism-induced increase in heart sphingomyelin (SM) concentration might be one of the mechanisms underlying maintenance of CER at relatively low level by its conversion to SM together with decreased S1P content.
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Ceramidas/metabolismo , Hipertiroidismo/metabolismo , Miocardio/metabolismo , Esfingomielinas/metabolismo , Triyodotironina/administración & dosificación , Animales , Ceramidasas/metabolismo , Modelos Animales de Enfermedad , Hipertiroidismo/inducido químicamente , Hipertiroidismo/enzimología , Lisofosfolípidos/metabolismo , Masculino , Ratas , Ratas Wistar , Esfingomielina Fosfodiesterasa/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Triyodotironina/farmacocinéticaRESUMEN
Reduced plasma LDL-cholesterol is a hallmark of hyperthyroidism and is caused by transcriptional stimulation of LDL receptors in the liver. Here, we investigated whether thyroid hormone (TH) actions involve other mechanisms that may also account for the reduction in LDL-cholesterol, including effects on proprotein convertase subtilisin/kexin type 9 (PCSK9) and bile acid synthesis. Twenty hyperthyroid patients were studied before and after clinical normalization, and the responses to hyperthyroidism were compared with those in 14 healthy individuals after 14 days of treatment with the liver-selective TH analog eprotirome. Both hyperthyroidism and eprotirome treatment reduced circulating PCSK9, lipoprotein cholesterol, apoB and AI, and lipoprotein(a), while cholesterol synthesis was stable. Hyperthyroidism, but not eprotirome treatment, markedly increased bile acid synthesis and reduced fibroblast growth factor (FGF) 19 and dietary cholesterol absorption. Eprotirome treatment, but not hyperthyroidism, reduced plasma triglycerides. Neither hyperthyroidism nor eprotirome treatment altered insulin, glucose, or FGF21 levels. TH reduces circulating PSCK9, thereby likely contributing to lower plasma LDL-cholesterol in hyperthyroidism. TH also stimulates bile acid synthesis, although this response is not critical for its LDL-lowering effect.
Asunto(s)
Ácidos y Sales Biliares/biosíntesis , Proproteína Convertasas/sangre , Serina Endopeptidasas/sangre , Hormonas Tiroideas/metabolismo , Adolescente , Adulto , Anciano , Anilidas/farmacología , Apolipoproteínas B/sangre , Ácidos y Sales Biliares/sangre , Ácidos y Sales Biliares/química , Glucemia/metabolismo , Composición Corporal/efectos de los fármacos , Colesterol/sangre , Femenino , Factor 9 de Crecimiento de Fibroblastos/sangre , Factores de Crecimiento de Fibroblastos/sangre , Humanos , Hipertiroidismo/sangre , Hipertiroidismo/enzimología , Hipertiroidismo/metabolismo , Insulina/sangre , Absorción Intestinal/efectos de los fármacos , Lipoproteína(a)/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Proproteína Convertasa 9 , Receptores de Hormona Tiroidea/agonistas , Adulto JovenRESUMEN
Epidemiological studies have demonstrated that n-3 polyunsaturated fatty acid (PUFA) consumption is associated with a reduced risk of atherosclerosis and hyperlipidemia. It is well known that lipid metabolism is also influenced by thyroid hormones. The aim of our study was to test whether n-3 PUFA supplementation (200 mg/kg of body weight/day for 6 weeks given intragastrically) would affect lipid metabolism in Lewis male rats with altered thyroid status. Euthyroid, hypothyroid, and hyperthyroid status of experimental groups was well defined by plasma levels of triiodothyronine, the activity of liver mitochondrial glycerol-3-phosphate dehydrogenase, and by relative heart weight. Fasting blood glucose levels were significantly higher in the hyperthyroid compared to the euthyroid and hypothyroid rats (5.0±0.2 vs. 3.7±0.4 and 4.4±0.2 mmol/l, respectively). In hyperthyroid animals, the concentration of plasma postprandial triglycerides was also increased compared to euthyroid and hypothyroid rats (0.9±0.1 vs. 0.5±0.1 and 0.4±0.1 mmol/l, respectively). On the other hand, hypothyroidism compared to euthyroid and hyperthyroid status was associated with elevated plasma levels of total cholesterol (2.6±0.2 vs. 1.5±0.1 and 1.6±0.1 mmol/l, respectively), LDL cholesterol (0.9±0.1 vs. 0.4±0.1 and 0.2±0.1 mmol/l, respectively) as well as HDL cholesterol (1.6±0.1 vs. 1.0±0.1 and 1.3±0.1 mmol/l, respectively). Supplementation of n-3 PUFA in the present study did not significantly modify either relative heart weight or glucose and lipid levels in any thyroid status.
Asunto(s)
Ácidos Grasos Omega-3/metabolismo , Hipertiroidismo/metabolismo , Hipotiroidismo/metabolismo , Metabolismo de los Lípidos , Animales , Colesterol/metabolismo , Suplementos Dietéticos/análisis , Ácidos Grasos Omega-3/administración & dosificación , Glicerolfosfato Deshidrogenasa/metabolismo , Humanos , Hipertiroidismo/enzimología , Hipotiroidismo/enzimología , Hígado/metabolismo , Masculino , Mitocondrias/enzimología , Mitocondrias/metabolismo , Ratas , Ratas Endogámicas Lew , Hormonas Tiroideas/metabolismoRESUMEN
The plasticity and vulnerability of the rat spinal cord (SC) during postnatal development has been less investigated compared to other CNS structures. In this study, we determined the effects of thyroid hormonal (TH) deficiency and excess on postnatal growth and neurochemical development of the rat SC. The growth as well as the specific and total activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes of the SC were determined in hypo- and hyperthyroid rat pups at postnatal (P) days P1, P5, P10 and P21 (weaning), and were compared to age-matched untreated normal controls. AChE is a cholinergic synaptic enzyme while BuChE is a metabolic enzyme mainly found in glial cells and neurovascular cells. The SC is rich in somatic motor, autonomic cholinergic neurons and associated interneurons. Daily subcutaneous injection of pups with thyroxine (T4) and administration of antithyroid goitrogen propylthiouracil (PTU) in the litter's drinking water were used to induce hyper- and hypothyroidism, respectively. Enzyme assays were carried out spectrophotometrically at the above-mentioned ages, using SC homogenates with acetylthiocholine-chloride as the substrate, together with specific cholinesterase inhibitors, which specifically target AChE and BuChE. SC weights were significantly lower at P10 and P21 in hypothyroid pups but unchanged in the hyperthyroid ones. Hypothyroidism significantly reduced both specific and total AChE activity in SC of P10 and P21 rat pups, while having no effects on the BuChE activity, although total BuChE activity was decreased due to reduced total tissue weight. In contrast both specific and total AChE activities were markedly and significantly increased (>100%) in the P10 and P21 hyperthyroid pups. However, BuChE specific activity was unaffected by this treatment. The results indicate that hypothyroid condition significantly reduces, while hyperthyroidism increases, the postnatal development of cholinergic synapses, thereby influencing the functional development of this major sensory and motor structure. However, the neurochemical development of glia and other non-neuronal cells, where BuChE is mainly localized, is comparatively unaffected in these abnormal developmental conditions.
Asunto(s)
Acetilcolinesterasa/fisiología , Butirilcolinesterasa/fisiología , Hipertiroidismo/enzimología , Hipotiroidismo/enzimología , Médula Espinal/enzimología , Médula Espinal/crecimiento & desarrollo , Animales , Animales Recién Nacidos , Antitiroideos , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Femenino , Hipertiroidismo/inducido químicamente , Hipertiroidismo/patología , Hipotiroidismo/inducido químicamente , Hipotiroidismo/patología , Embarazo , Propiltiouracilo , Ratas , Ratas Sprague-Dawley , TiroxinaRESUMEN
UNLABELLED: Oxidative stress is an important factor of the hyperthyroidism pathogenesis. The radioiodine therapy is an approved treatment method of this common disease and it is connected with exposure to ionizing radiation, which induces increased generation of reactive oxygen species in patient's organism. The aim of the study was to estimate the selected oxidative stress parameters in hyperthyroid patients, initially treated with thiamazole and subsequently with radioiodine. The evaluated parameters were the activity of superoxide dismutase (CuZn-SOD), catalase (CAT) and glutathione peroxidase (GPx) in erythrocytes as well as the level of total antioxidative status (TAS) in plasma. MATERIAL AND METHODS: In the study participated 29 healthy volunteers and 27 hyperthyroid patients, treated with thiamazole and prepared for radioiodine therapy. The antioxidant enzymes activity and the level of TAS were measured before administration of radioiodine therapeutic dose (average 18.47 +/- 8.81 mCi) as well as 30 days after treatment and achieving euthyreosis. RESULTS: Hyperthyroid patients prepared with thiamazole for radioiodine therapy demonstrated higher GPx activity (p < 0.0001) and lower TAS level (p < 0.0001) than healthy people. Patients, who become euthyroid after 30 days from radioiodine therapy, were characterised by the increased activity of CAT (p < 0.05) and GPx (p < 0.05) as well as the higher level of TAS (p < 0.05). Patients after radioiodine treatment in comparison to the control group had the same activity of CAT and the level of TAS, although the activity of CuZn-SOD (p < 0.05) and GPx (p < 0.0001) occurred higher than in the control group. Moreover patients with hyperthyroidism before radioiodine treatment showed positive correlation between the level of TSH and TAS, whereas after radioiodine therapy they demonstrated positive correlation between the level of TSH and the activity of CuZn-SOD, CAT and GPx. However, there was no statistically significant correlation between the quantity of administrated radioiodine dose and the value of estimated oxidative stress parameters. CONCLUSIONS: The results of the study show the occurrence of oxidative stress in hyperthyroid patients prepared with thiamazole to radioiodine therapy. Euthyreosis achieved by radioiodine treatment effected on normalisation of the activity of CAT and the level of TAS, although the activity of CuZn-SOD and GPx stayed increased. After the analysis of correlation between TSH level, radioiodine dose and measured parameters we can conclude that the intensity of oxidative stress more depends on current thyreometabolic state than on the therapeutic method applied.
Asunto(s)
Hipertiroidismo/enzimología , Hipertiroidismo/radioterapia , Radioisótopos de Yodo/uso terapéutico , Estrés Oxidativo , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Superóxido Dismutasa/sangreRESUMEN
Hyperthyroidism is characterized in rats by increased energy expenditure and marked hyperphagia. Alterations of thermogenesis linked to hyperthyroidism are associated with dysregulation of hypothalamic AMPK and fatty acid metabolism; however, the central mechanisms mediating hyperthyroidism-induced hyperphagia remain largely unclear. Here, we demonstrate that hyperthyroid rats exhibit marked up-regulation of the hypothalamic mammalian target of rapamycin (mTOR) signalling pathway associated with increased mRNA levels of agouti-related protein (AgRP) and neuropeptide Y (NPY), and decreased mRNA levels of pro-opiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC), an area where mTOR co-localizes with thyroid hormone receptor-α (TRα). Central administration of thyroid hormone (T3) or genetic activation of thyroid hormone signalling in the ARC recapitulated hyperthyroidism effects on feeding and the mTOR pathway. In turn, central inhibition of mTOR signalling with rapamycin in hyperthyroid rats reversed hyperphagia and normalized the expression of ARC-derived neuropeptides, resulting in substantial body weight loss. The data indicate that in the hyperthyroid state, increased feeding is associated with thyroid hormone-induced up-regulation of mTOR signalling. Furthermore, our findings that different neuronal modulations influence food intake and energy expenditure in hyperthyroidism pave the way for a more rational design of specific and selective therapeutic compounds aimed at reversing the metabolic consequences of this disease.
Asunto(s)
Ingestión de Alimentos , Conducta Alimentaria , Hiperfagia/etiología , Hipertiroidismo/complicaciones , Hipotálamo/enzimología , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Proteína Relacionada con Agouti/genética , Animales , Modelos Animales de Enfermedad , Ingestión de Alimentos/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Hiperfagia/enzimología , Hiperfagia/genética , Hiperfagia/fisiopatología , Hiperfagia/prevención & control , Hipertiroidismo/inducido químicamente , Hipertiroidismo/enzimología , Hipertiroidismo/genética , Hipertiroidismo/fisiopatología , Hipotálamo/efectos de los fármacos , Hipotálamo/fisiopatología , Masculino , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/enzimología , Neuropéptido Y/genética , Fosforilación , Proopiomelanocortina/genética , Inhibidores de Proteínas Quinasas/farmacología , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Receptores alfa de Hormona Tiroidea/metabolismo , Factores de Tiempo , Triyodotironina , Pérdida de PesoRESUMEN
Serum or plasma alanine aminotransferase (ALAT) activity may sometimes exhibit even considerable increases in connection with hyperthyroidism and present a diagnostic as well as a therapeutic problem. Open questions include whether the hepatic change is related to a primary disease, and how to select treatment. We report two patients, in whom carbimazole medication initiated for Graves' disease normalized elevated ALAT values.
Asunto(s)
Alanina Transaminasa/sangre , Antitiroideos/uso terapéutico , Carbimazol/uso terapéutico , Hipertiroidismo/tratamiento farmacológico , Hipertiroidismo/enzimología , Biomarcadores/sangre , HumanosRESUMEN
BACKGROUND: Hyperthyroidism increases heart rate, contractility, cardiac output, and metabolic rate. It is also accompanied by alterations in the regulation of cardiac substrate use. Specifically, hyperthyroidism increases the ex vivo activity of pyruvate dehydrogenase kinase, thereby inhibiting glucose oxidation via pyruvate dehydrogenase. Cardiac hypertrophy is another effect of hyperthyroidism, with an increase in the abundance of mitochondria. Although the hypertrophy is initially beneficial, it can eventually lead to heart failure. The aim of this study was to use hyperpolarized magnetic resonance spectroscopy to investigate the rate and regulation of in vivo pyruvate dehydrogenase flux in the hyperthyroid heart and to establish whether modulation of flux through pyruvate dehydrogenase would alter cardiac hypertrophy. METHODS AND RESULTS: Hyperthyroidism was induced in 18 male Wistar rats with 7 daily intraperitoneal injections of freshly prepared triiodothyronine (0.2 mg x kg(-1) x d(-1)). In vivo pyruvate dehydrogenase flux, assessed with hyperpolarized magnetic resonance spectroscopy, was reduced by 59% in hyperthyroid animals (0.0022 ± 0.0002 versus 0.0055 ± 0.0005 second(-1); P=0.0003), and this reduction was completely reversed by both short- and long-term delivery of dichloroacetic acid, a pyruvate dehydrogenase kinase inhibitor. Hyperpolarized [2-(13)C]pyruvate was also used to evaluate Krebs cycle metabolism and demonstrated a unique marker of anaplerosis, the level of which was significantly increased in the hyperthyroid heart. Cine magnetic resonance imaging showed that long-term dichloroacetic acid treatment significantly reduced the hypertrophy observed in hyperthyroid animals (100 ± 20 versus 200 ± 30 mg; P=0.04) despite no change in the increase observed in cardiac output. CONCLUSIONS: This work has demonstrated that inhibition of glucose oxidation in the hyperthyroid heart in vivo is mediated by pyruvate dehydrogenase kinase. Relieving this inhibition can increase the metabolic flexibility of the hyperthyroid heart and reduce the level of hypertrophy that develops while maintaining the increased cardiac output required to meet the higher systemic metabolic demand.