Tissue-Specific Suppression of Thyroid Hormone Signaling in Various Mouse Models of Aging.

DNA damage contributes to the process of aging, as underscored by premature aging syndromes caused by defective DNA repair. Thyroid state changes during aging, but underlying mechanisms remain elusive. Since thyroid hormone (TH) is a key regulator of metabolism, changes in TH signaling have widespread effects.

Left-ventricular remodeling after myocardial infarction is associated with a cardiomyocyte-specific hypothyroid condition.

Similarities in cardiac gene expression in hypothyroidism and left ventricular (LV) pathological remodeling after myocardial infarction (MI) suggest a role for impaired cardiac thyroid hormone (TH) signaling in the development of heart failure. Increased ventricular activity of the TH-degrading enzyme type 3 deiodinase (D3) is recognized as a potential cause. In the present study, we investigated the cardiac expression and activity of D3 over an 8-wk period after MI in C57Bl/6J mice.

Identification of molecular mechanisms related to nonthyroidal illness syndrome in skeletal muscle and adipose tissue from patients with septic shock.

Objective: Septic shock is one of various causes of nonthyroidal illness syndrome (NTIS). In humans, the molecular mechanisms involved in NTIS are mostly unknown. The aim of this study was to investigate, in patients with NTIS secondary to septic shock, changes in the expression of genes involved in the actions of thyroid hormones and in the activity of deiodinase enzymes, in two tissues important for protein and energy metabolism, skeletal muscle (SM) and subcutaneous adipose tissue (SAT).

Differential effects of maternal dexamethasone treatment on circulating thyroid hormone concentrations and tissue deiodinase activity in the pregnant ewe and fetus.

Clinically, treatment of pregnant women at risk of preterm delivery with synthetic glucocorticoids accelerates fetal maturation. This study investigated the effect of maternal dexamethasone treatment, in clinically relevant doses, on plasma thyroid hormone concentrations and tissue deiodinase activities (D1, D2, and D3) in ewes and their fetuses. From 125 d of gestation (term 145 +/- 2 d), pregnant ewes were injected twice im with either saline (2 ml of 0.

Developmental control of iodothyronine deiodinases by cortisol in the ovine fetus and placenta near term.

Preterm infants have low serum T4 and T3 levels, which may partly explain the immaturity of their tissues. Deiodinase enzymes are important in determining the bioavailability of thyroid hormones: deiodinases D1 and D2 convert T4 to T3, whereas deiodinase D3 inactivates T3 and produces rT3 from T4. In human and ovine fetuses, plasma T3 rises near term in association with the prepartum cortisol surge.

Increased thyroxine sulfate levels in critically ill patients as a result of a decreased hepatic type I deiodinase activity.

Introduction: Marked changes in peripheral thyroid hormone metabolism occur in critical illness, resulting in low serum T3 and high rT3 levels. In this study, we investigated whether T4S levels are increased in patients who died after intensive care and whether T4S levels are correlated with liver type I deiodinase (D1) or sulfotransferase (SULT) activity.

Methods: A total of 64 blood samples and 65 liver biopsies were obtained within minutes after death from 79 intensive care patients, randomized for intensive or conventional insulin treatment.

Tissue thyroid hormone levels in critical illness.

Context: Pronounced alterations in serum thyroid hormone levels occur during critical illness. T3 decreases and rT3 increases, the magnitudes of which are related to the severity of disease. It is unclear whether these changes are associated with decreased tissue T3 concentrations and, thus, reduced thyroid hormone bioactivity.

Serum 3,3',5'-triiodothyronine (rT3) and 3,5,3'-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities.

Introduction And Methods: Critical illness is associated with reduced TSH and thyroid hormone secretion, and with changes in peripheral thyroid hormone metabolism, resulting in low serum T3 and high rT3. In 451 critically ill patients who received intensive care for more than 5 d, serum thyroid parameters were determined on d 1, 5, 15, and last day (LD). All patients had been randomized for intensive or conventional insulin treatment.

Daily variations in type II iodothyronine deiodinase activity in the rat brain as controlled by the biological clock.

Type II deiodinase (D2) plays a key role in regulating thyroid hormone-dependent processes in, among others, the central nervous system (CNS) by accelerating the intracellular conversion of T4 into active T3. Just like the well-known daily rhythm of the hormones of the hypothalamo-pituitary-thyroid axis, D2 activity also appears to show daily variations. However, the mechanisms involved in generating these daily variations, especially in the CNS, are not known.

Characteristics and thyroid state-dependent regulation of iodothyronine deiodinases in pigs.

Three iodothyronine deiodinases (D1, D2, and D3) regulate local and systemic availability of thyroid hormone. D1 and D2 activate the prohormone T4 to the thyromimetic T3, and D3 inactivates T4 and T3 to rT3 and 3,3'-diiodothyronine, respectively. The expression of the three deiodinases is tightly regulated with regard to developmental stage and cell type to provide fine tuning of T3 supply to target cells.

Molecular basis for the substrate selectivity of cat type I iodothyronine deiodinase.

The type I iodothyronine deiodinase (D1) catalyzes the activation of T4 to T3 as well as the degradation of T3 (rT3) and sulfated iodothyronines. A comparison of the catalytic activities of D1 in liver microsomal preparations from several species revealed a remarkable difference between cat D1 on one hand and rat/human D1 on the other hand. The Michaelis constant (Km) of cat D1 for rT3 (11 microm) is 30-fold higher than that of rat and human D1 (0.

Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients.

Critical illness is often associated with reduced TSH and thyroid hormone secretion as well as marked changes in peripheral thyroid hormone metabolism, resulting in low serum T(3) and high rT(3) levels. To study the mechanism(s) of the latter changes, we determined serum thyroid hormone levels and the expression of the type 1, 2, and 3 iodothyronine deiodinases (D1, D2, and D3) in liver and skeletal muscle from deceased intensive care patients. To study mechanisms underlying these changes, 65 blood samples, 65 liver, and 66 skeletal muscle biopsies were obtained within minutes after death from 80 intensive care unit patients randomized for intensive or conventional insulin treatment.

Characterization of rat iodothyronine sulfotransferases.

Sulfation appears to be an important pathway for the reversible inactivation of thyroid hormone during fetal development. The rat is an often used animal model to study the regulation of fetal thyroid hormone status. The present study was done to determine which sulfotransferases (SULTs) are important for iodothyronine sulfation in the rat, using radioactive T4, T3, rT3, and 3,3'-T2 as substrates, 3'-phosphoadenosine-5'-phosphosulfate (PAPS) as cofactor, and rat liver, kidney and brain cytosol, and recombinant rat SULT1A1, -1B1, -1C1, -1E1, -2A1, -2A2, and -2A3 as enzymes.

Induction of thyroid hormone-degrading deiodinase in cardiac hypertrophy and failure.

The similarities between the changes in cardiac gene expression in pathological ventricular hypertrophy and hypothyroidism suggest a role of impaired cardiac thyroid hormone (TH) action in the development of contractile dysfunction during chronic cardiac pressure overload. Here we studied the possible involvement of altered cardiac TH metabolism using a rat model of right-ventricular (RV) hypertrophy induced by pressure-overload. Pathological RV hypertrophy was indicated by decreased mRNA levels of sarcoplasmic reticulum(SR) Ca2-ATPase type 2a (SERCA2a) and myosin heavy chain a (MHCalpha), and increased levels of MHCbeta mRNA.

Characterization of iodothyronine sulfatase activities in human and rat liver and placenta.

In conditions associated with high serum iodothyronine sulfate concentrations, e.g. during fetal development, desulfation of these conjugates may be important in the regulation of thyroid hormone homeostasis.