scholarly journals Stimulatory Effects of Thyroid Hormone on Brain Angiogenesis in vivo and in vitro

2009 ◽  
Vol 30 (2) ◽  
pp. 323-335 ◽  
Author(s):  
Liqun Zhang ◽  
Christiana Marie Cooper-Kuhn ◽  
Ulf Nannmark ◽  
Klas Blomgren ◽  
Hans Georg Kuhn
Keyword(s):  
Growth Factor ◽  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Hormone Deficiency ◽  
Mrna Levels ◽  
Substantial Impact ◽  
Altered Expression ◽  
Brain Angiogenesis

Thyroid hormone is critical for the proper development of the central nervous system. However, the specific role of thyroid hormone on brain angiogenesis remains poorly understood. Treatment of rats from birth to postnatal day 21 (P21) with propylthiouracil (PTU), a reversible blocker of triiodothyronine (T3) synthesis, resulted in decreased brain angiogenesis, as indicated by reduced complexity and density of microvessels. However, when PTU was withdrawn at P22, these parameters were fully recovered by P90. These changes were paralleled by an altered expression of vascular endothelial growth factor A ( Vegfa) and basic fibroblast growth factor ( Fgf2). Physiologic concentrations of T3 and thyroxine (T4) stimulated proliferation and tubulogenesis of rat brain-derived endothelial (RBE4) cells in vitro. Protein and mRNA levels of VEGF-A and FGF-2 increased after T3 stimulation of RBE4 cells. The thyroid hormone receptor blocker NH-3 abolished T3-induced Fgf2 and Vegfa upregulation, indicating a receptor-mediated effect. Thyroid hormone inhibited the apoptosis in RBE4 cells and altered mRNA levels of apoptosis-related genes, namely Bcl2 and Bad. The present results show that thyroid hormone has a substantial impact on vasculature development in the brain. Pathologically altered vascularization could, therefore, be a contributing factor to the neurologic deficits induced by thyroid hormone deficiency.

Effect of chronic energy deprivation on cardiac thyroid hormone receptor and myosin isoform expression

1994 ◽  
Vol 266 (2) ◽  
pp. E254-E260 ◽  
Author(s):  
S. J. Swoap ◽  
F. Haddad ◽  
P. Bodell ◽  
K. M. Baldwin
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Binding Capacity ◽  
Relative Content ◽  
Female Rats ◽  
Mrna Levels ◽  
Isoform Expression ◽  
Energy Deprivation

Thyroid hormone (3,5,3'-triiodothyronine; T3) and its receptor (TR) play an important regulatory role for in vivo and in vitro cardiac myosin heavy chain (MHC) isoform gene expression by activating the alpha- and inhibiting the beta-MHC genes. Previous studies have shown that chronic energy deprivation (CED; 50% of normal caloric intake) in the rat impacts cardiac MHC protein expression and hemodynamic parameters in a pattern typically seen with hypothyroidism; yet, unlike hypothyroidism, circulating T3 levels are not depressed. Therefore, the goal of this study was to determine if the altered MHC isoform expression observed in CED is associated with altered TR expression, both at the mRNA and protein levels. Female rats weighing approximately 250 g were allocated into two groups, designated as normal control (NC) and CED. After 5 wk, the relative content of alpha-MHC protein and mRNA levels decreased in CED ventricles by 20% (P < 0.05). In contrast, the relative content of both beta-MHC protein and mRNA levels increased five- to sixfold in CED (P < 0.05). Although there were no changes in TR mRNA levels relative to 18S rRNA in CED, the total number of nuclear TRs decreased 3.5-fold in the CED group (P < 0.05), from a maximum binding capacity of 840 +/- 130 fmol/mg DNA in NC to 241 +/- 118 fmol/mg DNA in CED, with no change in the affinity of the receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Tri-iodothyronine increases insulin-like growth factor binding protein-2 expression in cultured hepatocytes from hypothyroid rats

1999 ◽  
Vol 161 (3) ◽  
pp. 465-474 ◽  
Author(s):  
I Demori ◽  
C Bottazzi ◽  
E Fugassa
Keyword(s):  
Growth Factor ◽  
Thyroid Hormone ◽  
Binding Protein ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Insulin Like Growth Factor ◽  
Cultured Hepatocytes ◽  
Factor Binding

Previous evidence suggests the existence of a thyroid hormone-IGF axis in the liver and changes in hepatic insulin-like growth factor binding protein (IGFBP) expression in rats with altered thyroid status have been previously reported. The aim of this study was to check if the higher IGFBP-2 mRNA levels observed in liver of hypothyroid rats could be due to a direct effect of thyroid hormone on the IGFBP-2 gene. In our experiments, cultured hepatocytes isolated from normal and hypothyroid adult rats were used. Northern blot analysis revealed barely detectable IGFBP-2 mRNA in normal rat hepatocytes, but easily detectable signal in hypothyroid rat cells. Therefore, the effect of tri-iodothyronine (T3) was investigated using cultured hepatocytes from hypothyroid rats as an in vitro model. The IGFBP-2 message was increased in a dose-dependent manner in hepatocytes cultured for 12-24 h in the presence of T3. A similar increase occurred in accumulation of IGFBP-2 in the culture medium, as measured by RIA. The effect of T3 on IGFBP-2 transcript levels appeared to consist of enhanced gene transcription and was independent of ongoing protein synthesis, but it was completely abolished by the incubation of hepatocytes with insulin. The latter result confirmed the dominant role of insulin in regulating IGFBP-2 expression by cultured hepatocytes. In vivo experiments confirmed an increase in hepatic IGFBP-2 mRNA and serum IGFBP-2 levels in hypothyroid rats and demonstrated, in addition, a significant increase in these measures in T3-treated rats. Taken together, our in vitro and in vivo results support a role for a thyroid hormone-IGF axis in the liver and suggest that other factors, such as insulin, interact in vivo with thryoid hormone in regulating hepatic IGFBP-2 expression.

Suppression of Angiogenesis and Resistance to Doxorubicin by the Thyroid Hormone Tetraiodothyroacetic Acid.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4209-4209
Author(s):  
Shaker A. Mousa ◽  
Laura O’Connor ◽  
Ahmad Aljada ◽  
Paul Davis ◽  
Abdelhadi Rebbaa
Keyword(s):  
Drug Resistance ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Thyroid Hormone ◽  
Chorioallantoic Membrane ◽  
Mrna Levels ◽  
Vascular Endothelial ◽  
Resistance To Doxorubicin

Abstract Thyroid hormone has been recently shown to induce tumor growth and angiogenesis. These angiogenesis modulating activities are initiated at endothelial cell plasma membrane receptor via the integrin αVβ3, at or near the Arg-Gly-Asp (RGD) recognition site on the integrin. In the present study, we have investigated the effect of tetraiodothyroacetic acid (tetrac), a deaminated thyroid hormone analog that inhibits thyroid hormone-binding to the cell surface integrin, on angiogenesis and cancer cell resistance to doxorubicin both in vitro and in vivo. Two angiogenesis models were studied in which vascular endothelial growth factor, VEGF165 or basic fibroblast growth factor, FGF2 (1–2 μg/ml) or thyroid hormone, thyroxin (L-T4 or T3) were used either to induce tube formation in the human dermal micro-vascular endothelial cells (HDMEC), or to stimulate new blood vessel branch formation in the chick chorioallantoic membrane (CAM) models. In both models, Tetrac (0.1–10 μM) inhibited the pro-angiogenesis activity of VEGF, FGF2, L-T4 or T3 by more than 50% at 1.0 uM RT-PCR revealed that tetrac (1–3 μM) decreased abundance of angiopoietin-2 mRNA but did not affect the mRNA levels of angiopoietin-1, in VEGF-exposed endothelial cells, suggesting that specific angiogenic pathways are targeted by this compound. Additionally, microarray was used to examine changes in expression of Matrix Metalloproteinases (MMP) and Tissue Inhibitor of Metalloproteinases (TIMP) following VEGF treatment with and without tetrac. HDMEC cells treated with VEGF exhibited 3–5-fold increase in MMP-15 and MMP-19 expression and tetrac (3μM), inhibited expression of MMP-15 and MMP-19 by 3–9-fold, respectively. Expression of TIMP-3 was increased 5.4-fold following VEGF and tetrac treatment when compared to treatment with VEGF alone. This finding suggests that part of the mechanism by which tetrac inhibits VEGF-stimulated angiogenesis involves inhibition of certain MMPs and increase in TIMP expression. Investigation of the anti-proliferative function of tetrac was carried out using the αVβ3 expressing breast cancer cells MC7 and their drug resistant counterparts. Interestingly, proliferation of both cell lines was inhibited similarly by tetrac suggesting that this analog may circumvent drug resistance. In fact, tetrac was able to reverse resistance to doxorubicin in vitro and to suppress growth of doxorubicin resistant tumors in nude mice. Inhibition of the drug transporter p-glycoprotein was found to play a key role in mediating the action of tetrac. Taken together, findings presented in this study provide evidence that the anticancer function of tetrac can be attributed to its anti-angiogenic and drug resistance reversal activities.

scholarly journals Thyroid hormone receptor regulates most genes independently of fibroblast growth factor 21 in liver

2014 ◽  
Vol 224 (3) ◽  
pp. 289-301 ◽  
Author(s):  
Aijun Zhang ◽  
Douglas H Sieglaff ◽  
Jean Philippe York ◽  
Ji Ho Suh ◽  
Stephen D Ayers ◽  
...  
Keyword(s):  
Growth Factor ◽  
Thyroid Hormone ◽  
Fibroblast Growth Factor ◽  
Thyroid Hormone Receptor ◽  
Expression Profiles ◽  
Fibroblast Growth Factor 21 ◽  
Small Subset ◽  
Fibroblast Growth ◽  
Serum Triglycerides

Thyroid hormone (TH) acts through specific receptors (TRs), which are conditional transcription factors, to induce fibroblast growth factor 21 (FGF21), a peptide hormone that is usually induced by fasting and that influences lipid and carbohydrate metabolism via local hepatic and systemic endocrine effects. While TH and FGF21 display overlapping actions when administered, including reductions in serum lipids, according to the current models these hormones act independentlyin vivo. In this study, we examined mechanisms of regulation of FGF21 expression by TH and tested the possibility that FGF21 is required for induction of hepatic TH-responsive genes. We confirm that active TH (triiodothyronine (T3)) and the TRβ-selective thyromimetic GC1 increase FGF21 transcript and peptide levels in mouse liver and that this effect requires TRβ. T3also induces FGF21 in cultured hepatocytes and this effect involves direct actions of TRβ1, which binds a TRE within intron 2 of FGF21. Gene expression profiles of WT andFgf21-knockout mice are very similar, indicating that FGF21 is dispensable for the majority of hepatic T3gene responses. A small subset of genes displays diminished T3response in the absence of FGF21. However, most of these are not obviously directly involved in T3-dependent hepatic metabolic processes. Consistent with these results, T3-dependent effects on serum cholesterol are maintained in theFgf21−/−background and we observe no effect of theFgf21-knockout background on serum triglycerides and glucose. Our findings indicate that T3regulates the genes involved in classical hepatic metabolic responses independently of FGF21.

scholarly journals Regulation of gene transcription by thyroid hormone receptor β agonists in clinical development for the treatment of non-alcoholic steatohepatitis (NASH)

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0240338
Author(s):  
Xuan G. Luong ◽  
Sarah K. Stevens ◽  
Andreas Jekle ◽  
Tse-I Lin ◽  
Kusum Gupta ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Fatty Acid Biosynthesis ◽  
Thyroid Hormone Receptor ◽  
Density Lipoprotein ◽  
Liver Fat ◽  
Alcoholic Steatohepatitis

Thyroid hormones are important modulators of metabolic activity in mammals and alter cholesterol and fatty acid levels through activation of the nuclear thyroid hormone receptor (THR). Currently, there are several THRβ agonists in clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) that have demonstrated the potential to reduce liver fat and restore liver function. In this study, we tested three THRβ-agonism-based NASH treatment candidates, GC-1 (sobetirome), MGL-3196 (resmetirom), and VK2809, and compared their selectivity for THRβ and their ability to modulate the expression of genes specific to cholesterol and fatty acid biosynthesis and metabolism in vitro using human hepatic cells and in vivo using a rat model. Treatment with GC-1 upregulated the transcription of CPT1A in the human hepatocyte-derived Huh-7 cell line with a dose-response comparable to that of the native THR ligand, triiodothyronine (T3). VK2809A (active parent of VK2809), MGL-3196, and VK2809 were approximately 30-fold, 1,000-fold, and 2,000-fold less potent than T3, respectively. Additionally, these relative potencies were confirmed by quantification of other direct gene targets of THR, namely, ANGPTL4 and DIO1. In primary human hepatocytes, potencies were conserved for every compound except for VK2809, which showed significantly increased potency that was comparable to that of its active counterpart, VK2809A. In high-fat diet fed rats, a single dose of T3 significantly reduced total cholesterol levels and concurrently increased liver Dio1 and Me1 RNA expression. MGL-3196 treatment resulted in concentration-dependent decreases in total and low-density lipoprotein cholesterol with corresponding increases in liver gene expression, but the compound was significantly less potent than T3. In conclusion, we have implemented a strategy to rank the efficacy of THRβ agonists by quantifying changes in the transcription of genes that lead to metabolic alterations, an effect that is directly downstream of THR binding and activation.

scholarly journals Dronerarone Acts as a Selective Inhibitor of 3,5,3′-Triiodothyronine Binding to Thyroid Hormone Receptor-α1: In Vitro and in Vivo Evidence

Endocrinology ◽  
2003 ◽  
Vol 144 (2) ◽  
pp. 552-558 ◽  
Author(s):  
H. C. van Beeren ◽  
W. M. C. Jong ◽  
E. Kaptein ◽  
T. J. Visser ◽  
O. Bakker ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Density Lipoprotein ◽  
Inhibitory Effect ◽  
Selective Inhibitor ◽  
Receptor Protein ◽  
Qtc Interval

Dronedarone (Dron), without iodine, was developed as an alternative to the iodine-containing antiarrhythmic drug amiodarone (AM). AM acts, via its major metabolite desethylamiodarone, in vitro and in vivo as a thyroid hormone receptor α1 (TRα1) and TRβ1 antagonist. Here we investigate whether Dron and/or its metabolite debutyldronedarone inhibit T3 binding to TRα1 and TRβ1in vitro and whether dronedarone behaves similarly to amiodarone in vivo. In vitro , Dron had a inhibitory effect of 14% on the binding of T3 to TRα1, but not on TRβ1. Desethylamiodarone inhibited T3 binding to TRα1 and TRβ1 equally. Debutyldronedarone inhibited T3 binding to TRα1 by 77%, but to TRβ1 by only 25%. In vivo , AM increased plasma TSH and rT3, and decreased T3. Dron decreased T4 and T3, rT3 did not change, and TSH fell slightly. Plasma total cholesterol was increased by AM, but remained unchanged in Dron-treated animals. TRβ1-dependent liver low density lipoprotein receptor protein and type 1 deiodinase activities decreased in AM-treated, but not in Dron-treated, animals. TRα1-mediated lengthening of the QTc interval was present in both AM- and Dron-treated animals. The in vitro and in vivo findings suggest that dronedarone via its metabolite debutyldronedarone acts as a TRα1-selective inhibitor.

scholarly journals Thyroid hormone-stimulated differentiation of primary rib chondrocytes in vitro requires thyroid hormone receptor β

2006 ◽  
Vol 191 (1) ◽  
pp. 221-228 ◽  
Author(s):  
Bénédicte Rabier ◽  
Allan J Williams ◽  
Frederic Mallein-Gerin ◽  
Graham R Williams ◽  
O Chassande
Keyword(s):  
Thyroid Hormone ◽  
Growth Plate ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Primary Cultures ◽  
Wild Type ◽  
Proliferation And Differentiation ◽  
Thyroid Hormone Receptor Β

The active thyroid hormone, triiodothyronine (T3), binds to thyroid hormone receptors (TR) and plays an essential role in the control of chondrocyte proliferation and differentiation. Hypo- and hyperthyroidism alter the structure of growth plate cartilage and modify chondrocyte gene expression in vivo, whilst TR mutations or deletions in mice result in altered growth plate architecture. Nevertheless, the particular roles of individual TR isoforms in mediating T3 action in chondrocytes have not been studied and are difficult to determine in vivo because of complex cellular and molecular interactions that regulate growth plate maturation. Therefore, we studied the effects of TRα and TRβ on chondrocyte growth and differentiation in primary cultures of neonatal rib chondrocytes isolated from TRα- and TRβ-deficient mice. T3 decreased proliferation but accelerated differentiation of rib chondrocytes from wild-type mice. T3 treatment resulted in similar effects in TRα-deficient chondrocytes, but in TRβ-deficient chondrocytes, all T3 responses were abrogated. Furthermore, T3 increased TRβ1 expression in wild-type and TRα-deficient chondrocytes. These data indicate that T3-stimulated differentiation of primary rib chondrocytes in vitro requires TRβ and suggest that the TRβ1 isoform mediates important T3 actions in mouse rib chondrocytes.

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