scholarly journals Thyroid hormone receptor-α and vascular function

2012 ◽  
Vol 302 (9) ◽  
pp. C1346-C1352 ◽  
Author(s):  
Ayako Makino ◽  
Hong Wang ◽  
Brian T. Scott ◽  
Jason X.-J. Yuan ◽  
Wolfgang H. Dillmann
Keyword(s):  
Thyroid Hormone ◽  
Vascular Function ◽  
Vascular Tone ◽  
Thyroid Hormone Receptor ◽  
Contractile Function ◽  
Dependent Manner ◽  
Channel Activity ◽  
Cardiac Contractile Function ◽  
Vascular Contraction ◽  
Regulation Of Vascular Tone

Thyroid hormone (TH) treatment exerts beneficial effects on the cardiovascular system: it lowers cholesterol and LDL levels and enhances cardiac contractile function. However, little is known about the effect of TH on vascular function or the functional role of TH receptors (TRs) in the regulation of vascular tone. We have investigated the contribution of TRs to vascular contractility in the heart. Among different TR subtype-specific knockout (KO) mice, vascular contraction was significantly enhanced in coronary arteries isolated from TRα KO compared with wild-type mice, while chronic TH treatment significantly attenuated coronary vascular contraction. We found that TRα is the predominant TR in mouse coronary smooth muscle cells (SMCs). Coronary SMCs isolated from TRα KO mice exhibited a significant decrease in K+channel activity, whereas TH treatment increased K+channel activity in a dose-dependent manner. These data suggest that TRα in SMCs has prominent effects on regulation of vascular tone and TH treatment helps decrease coronary vascular tone by increasing K+channel activity through TRα in SMCs.

Coronary microvascular protection with Mg2+: effects on intracellular calcium regulation and vascular function

1999 ◽  
Vol 276 (4) ◽  
pp. H1124-H1130 ◽  
Author(s):  
Naruto Matsuda ◽  
Motohisa Tofukuji ◽  
Kathleen G. Morgan ◽  
Frank W. Sellke
Keyword(s):  
Intracellular Calcium ◽  
Vascular Function ◽  
Contractile Function ◽  
Dependent Manner ◽  
Vascular Contraction ◽  
Luminal Diameter ◽  
Intracellular Ca ◽  
Beneficial Action ◽  
Intracellular Calcium Regulation

The use of Mg2+-supplemented hyperkalemic cardioplegia preserves microvascular function. However, the mechanism of this beneficial action remains to be elucidated. We investigated the effects of Mg2+supplementation on the regulation of intracellular calcium concentration ([Ca2+]i) and vascular function using an in vitro microvascular model. Ferret coronary arterioles (80–150 μm in diameter) were studied in a pressurized (40 mmHg) no-flow, normothermic (37°C) state. Simultaneous monitoring of internal luminal diameter and [Ca2+]iusing fura 2 were made with microscopic image analysis. The microvessels ( n = 6 each group) were divided into four groups according to the content of MgCl2(nominally 0, 1.2, 5.0, and 25.0 mM) in a hyperkalemic cardioplegic solution ([K+] 25.0 mM). After baseline measurements, vessels were subjected to 60 min of hypoxia with hyperkalemic cardioplegia (equilibrated with 95% N2-5% CO2) containing each concentration of Mg2+([Mg2+]) and were then reoxygenated. During hyperkalemic cardioplegia, [Ca2+]iincreased in a time-dependent manner in all groups. In the lower [Mg2+] cardioplegia groups, [Ca2+]iwas significantly increased at the end of the 60-min cardioplegic period (247 ± 44 nM and 236 ± 49 nM in [Mg2+] 0 and 1.2 mM groups, respectively; both P < 0.05 vs. baseline) with 19.6–17.2% vascular contraction. Conversely, there was no significant [Ca2+]iincrease in the higher [Mg2+] cardioplegia groups and less vascular contraction (5.4–4.1%, both P < 0.05 vs. [Mg2+] 1.2 mM group). After reperfusion, agonist (U-46619, thromboxane A2analog)-induced vascular contraction was significantly enhanced in the lower [Mg2+] cardioplegia groups (both P < 0.05 vs. control) but was normalized in the higher [Mg2+] cardioplegia groups. Intrinsic myogenic contraction was significantly decreased in the lower [Mg2+] cardioplegia groups (both P < 0.05 vs. control) but was preserved in the higher [Mg2+] cardioplegia groups. These results suggest that supplementation of the solution with >5.0 mM [Mg2+] may prevent hyperkalemic cardioplegia-related intracellular Ca2+overloading and preserve vascular contractile function in coronary microvessels.

Ligand-mediated decrease of thyroid hormone receptor-α1 in cardiomyocytes by proteosome-dependent degradation and altered mRNA stability

2005 ◽  
Vol 288 (2) ◽  
pp. H813-H821 ◽  
Author(s):  
Agnes Kenessey ◽  
Kaie Ojamaa
Keyword(s):  
Thyroid Hormone ◽  
Mrna Stability ◽  
Hormone Receptor ◽  
Half Life ◽  
Thyroid Hormone Receptor ◽  
Contractile Function ◽  
Neonatal Rat ◽  
Maximum Effect ◽  
Cardiac Contractile Function ◽  
Mrna Half Life

Tri-iodo-l-thyronine (T3) is essential for maintaining normal cardiac contractile function by regulating transcription of numerous T3-responsive genes. Both hormone availability and relative amounts of nuclear thyroid hormone receptor isoforms (TRα1, TRβ1) determine T3 effectiveness. Cultured neonatal rat ventricular myocytes grown in T3-depleted medium expressed predominantly TRα1 protein, but within 4 h of T3 treatment, TRβ1 protein increased significantly, whereas TRα1 was decreased by 46 ± 5%. Using replication-defective adenoviruses to overexpress TRα1 in cardiomyocytes, we studied the mechanisms by which T3 mediated the decrease in TRα1 protein. Inhibitors of the proteosome pathway resulted in an accumulation of ubiquitylated TRα1 in the nucleus and prevented T3-induced degradation of ubiquitylated TRα1, suggesting that T3 induced proteosome-mediated degradation of TRα1; however, TR ubiquitylation was T3 independent. TRα1 transcriptional activity, measured using transient transfection of a thyroid hormone-responsive element (TRE) reporter plasmid, was T3 dose dependent and inversely proportional to nuclear TRα1 content, with 10 nM T3 having maximum effect. Quantitative RT-PCR showed that both endogenous and adenovirus-expressed TRα1 mRNAs were significantly decreased to 54 ± 11 and 25 ± 5%, respectively, within 4 h of T3 treatment. Measurements of TRα1 mRNA half-life in actinomycin D-treated cardiomyocytes showed that T3 treatment significantly decreased TRα1 mRNA half-life from 4 h to less than 2 h, whereas it had no effect of TRβ1 mRNA half-life. These data support a role for both the proteosome degradation pathway and altered mRNA stability in T3-induced decrease of nuclear TRα1 in the cardiomyocyte and provide novel cellular targets for therapeutic development.

A conserved C-terminal sequence that is deleted in v-ErbA is essential for the biological activities of c-ErbA (the thyroid hormone receptor)

1993 ◽  
Vol 13 (6) ◽  
pp. 3675-3685
Author(s):  
F Saatcioglu ◽  
P Bartunek ◽  
T Deng ◽  
M Zenke ◽  
M Karin
Keyword(s):  
Amino Acid ◽  
Thyroid Hormone ◽  
Transcriptional Activation ◽  
Thyroid Hormone Receptor ◽  
Retinoic Acid Receptor ◽  
Biological Activities ◽  
Erythroid Differentiation ◽  
Dependent Manner ◽  
Transcriptional Interference ◽  
Terminal Sequence

The thyroid hormone (T3) receptor type alpha, the c-ErbA alpha proto-oncoprotein, stimulates transcription of T3-dependent promoters, interferes with AP-1 activity, and induces erythroid differentiation in a ligand-dependent manner. The v-ErbA oncoprotein does not bind hormone and has lost all of these activities. Using c-ErbA/v-ErbA chimeras, we found that a deletion of 9 amino acids, conserved among many members of the nuclear receptor superfamily, which are located at the extreme carboxy terminus of c-ErbA alpha is responsible for loss of both transactivation and transcriptional interference activities. Single, double, and triple amino acid substitutions within this region completely abolished T3-dependent transcriptional activation, interference with AP-1 activity, and decreased T3 binding by c-ErbA alpha. However, the lower T3 binding by these mutants does not fully account for the loss of transactivation and transcriptional interference, since a c-ErbA/v-ErbA chimera which was similarly reduced in T3 binding activity has retained both of these functions. Deletion of homologous residues in the retinoic acid receptor alpha (RAR alpha) resulted in a similar loss of transactivation and transcriptional interference activities. The ability of c-ErbA alpha to induce differentiation of transformed erythroblasts is also impaired by all of the mutations introduced into the conserved carboxy-terminal sequence. We conclude that this 9-amino-acid conserved region is essential for normal biological function of c-ErbA alpha and RAR alpha and possibly other T3 and RA receptors.

scholarly journals A conserved C-terminal sequence that is deleted in v-ErbA is essential for the biological activities of c-ErbA (the thyroid hormone receptor).

1993 ◽  
Vol 13 (6) ◽  
pp. 3675-3685 ◽  
Author(s):  
F Saatcioglu ◽  
P Bartunek ◽  
T Deng ◽  
M Zenke ◽  
M Karin
Keyword(s):  
Amino Acid ◽  
Thyroid Hormone ◽  
Transcriptional Activation ◽  
Thyroid Hormone Receptor ◽  
Retinoic Acid Receptor ◽  
Biological Activities ◽  
Erythroid Differentiation ◽  
Dependent Manner ◽  
Transcriptional Interference ◽  
Terminal Sequence

The thyroid hormone (T3) receptor type alpha, the c-ErbA alpha proto-oncoprotein, stimulates transcription of T3-dependent promoters, interferes with AP-1 activity, and induces erythroid differentiation in a ligand-dependent manner. The v-ErbA oncoprotein does not bind hormone and has lost all of these activities. Using c-ErbA/v-ErbA chimeras, we found that a deletion of 9 amino acids, conserved among many members of the nuclear receptor superfamily, which are located at the extreme carboxy terminus of c-ErbA alpha is responsible for loss of both transactivation and transcriptional interference activities. Single, double, and triple amino acid substitutions within this region completely abolished T3-dependent transcriptional activation, interference with AP-1 activity, and decreased T3 binding by c-ErbA alpha. However, the lower T3 binding by these mutants does not fully account for the loss of transactivation and transcriptional interference, since a c-ErbA/v-ErbA chimera which was similarly reduced in T3 binding activity has retained both of these functions. Deletion of homologous residues in the retinoic acid receptor alpha (RAR alpha) resulted in a similar loss of transactivation and transcriptional interference activities. The ability of c-ErbA alpha to induce differentiation of transformed erythroblasts is also impaired by all of the mutations introduced into the conserved carboxy-terminal sequence. We conclude that this 9-amino-acid conserved region is essential for normal biological function of c-ErbA alpha and RAR alpha and possibly other T3 and RA receptors.

scholarly journals Inhibition of Estrogen Receptor Action by the Orphan Receptor SHP (Short Heterodimer Partner)

1998 ◽  
Vol 12 (10) ◽  
pp. 1551-1557 ◽  
Author(s):  
Wongi Seol ◽  
Bettina Hanstein ◽  
Myles Brown ◽  
David D. Moore
Keyword(s):  
Estrogen Receptor ◽  
Thyroid Hormone ◽  
Transcriptional Activation ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Orphan Receptor ◽  
Estrogen Signaling ◽  
Dependent Manner ◽  
Interaction Domain ◽  
Short Heterodimer Partner

Abstract SHP (short heterodimer partner) is an unusual orphan receptor that lacks a conventional DNA-binding domain. Previous results have shown that it interacts with several other nuclear hormone receptors, including the retinoid and thyroid hormone receptors, and inhibits their ligand-dependent transcriptional activation. Here we show that SHP also interacts with estrogen receptors and inhibits their function. In mammalian and yeast two-hybrid systems as well as glutathione-S-transferase pull-down assays, SHP interacts specifically with estrogen receptor-α (ERα) in an agonist-dependent manner. The same assay systems using various deletion mutants of SHP map the interaction domain with ERα to the same SHP sequences required for interaction with the nonsteroid hormone receptors such as retinoid X receptor and thyroid hormone receptor. In transient cotransfection assays, SHP inhibits estradiol -dependent activation by ERα by about 5-fold. In contrast, SHP interacts with ERβ independent of ligand and reduces its ability to activate transcription by only 50%. These data suggest that SHP functions to regulate estrogen signaling through a direct interaction with ERα.

scholarly journals The Trifunctional Protein Mediates Thyroid Hormone Receptor-Dependent Stimulation of Mitochondria Metabolism

2012 ◽  
Vol 26 (7) ◽  
pp. 1117-1128 ◽  
Author(s):  
E. Sandra Chocron ◽  
Naomi L. Sayre ◽  
Deborah Holstein ◽  
Nuttawut Saelim ◽  
Jamal A. Ibdah ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Thyroid Hormone ◽  
Protein Kinase ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Mitochondrial Metabolism ◽  
Dependent Manner ◽  
Compound C ◽  
Amp Activated Protein Kinase ◽  
Stimulation Of

Abstract We previously demonstrated that the thyroid hormone, T3, acutely stimulates mitochondrial metabolism in a thyroid hormone receptor (TR)-dependent manner. T3 has also recently been shown to stimulate mitochondrial fatty acid oxidation (FAO). Here we report that TR-dependent stimulation of metabolism is mediated by the mitochondrial trifunctional protein (MTP), the enzyme responsible for long-chain FAO. Stimulation of FAO was significant in cells that expressed a nonnuclear amino terminus shortened TR isoform (sTR43) but not in adult fibroblasts cultured from mice deficient in both TRα and TRβ isoforms (TRα−/−β−/−). Mouse embryonic fibroblasts deficient in MTP (MTP−/−) did not support T3-stimulated FAO. Inhibition of fatty-acid trafficking into mitochondria using the AMP-activated protein kinase inhibitor 6-[4-(2-piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyrrazolo[1,5-a]-pyrimidine (compound C) or the carnitine palmitoyltransferase 1 inhibitor etomoxir prevented T3-stimulated FAO. However, T3 treatment could increase FAO when AMP-activated protein kinase was maximally activated, indicating an alternate mechanism of T3-stimulated FAO exists, even when trafficking is presumably high. MTPα protein levels and higher molecular weight complexes of MTP subunits were increased by T3 treatment. We suggest that T3-induced increases in mitochondrial metabolism are at least in part mediated by a T3-shortened TR isoform-dependent stabilization of the MTP complex, which appears to lower MTP subunit turnover.

scholarly journals Regulation of thyroid hormone activation via the liver X-receptor/retinoid X-receptor pathway

2010 ◽  
Vol 205 (2) ◽  
pp. 179-186 ◽  
Author(s):  
Marcelo A Christoffolete ◽  
Márton Doleschall ◽  
Péter Egri ◽  
Zsolt Liposits ◽  
Ann Marie Zavacki ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Liver X Receptor ◽  
Retinoid X Receptor ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Diet Induced Obesity ◽  
Ectopic Liver ◽  
Dose Dependent

Thyroid hormone receptor (TR) and liver X-receptor (LXR) are the master regulators of lipid metabolism. Remarkably, a mouse with a targeted deletion of both LXRα and LXRβ is resistant to western diet-induced obesity, and exhibits ectopic liver expression of the thyroid hormone activating type 2 deiodinase (D2). We hypothesized that LXR/retinoid X-receptor (RXR) signaling inhibits hepatic D2 expression, and studied this using a luciferase reporter containing the human DIO2 (hDIO2) promoter in HepG2 cells. Given that, in contrast to mammals, the chicken liver normally expresses D2, the chicken DIO2 (cDIO2) promoter was also studied. 22(R)-OH-cholesterol negatively regulated hDIO2 in a dose-dependent manner (100 μM, approximately twofold), while it failed to affect the cDIO2 promoter. Truncations in the hDIO2 promoter identified the region −901 to −584 bp as critical for negative regulation. We also investigated if 9-cis retinoic acid (9-cis RA), the ligand for the heterodimeric partner of TR and LXR, RXR, could regulate the hDIO2 promoter. Notably, 9-cis RA repressed the hDIO2 luciferase reporter (1 μM, approximately fourfold) in a dose-dependent manner, while coexpression of an inactive mutant RXR abolished this effect. However, it is unlikely that RXR homodimers mediate the repression of hDIO2 since mutagenesis of a DR-1 at −506 bp did not interfere with 9-cis RA-mediated repression. Our data indicate that hDIO2 transcription is negatively regulated by both 22(R)-OH-cholesterol and 9-cis RA, which is consistent with LXR/RXR involvement. In vivo, the inhibition of D2-mediated tri-iodothyronine (T3) production by cholesterol/9-cis RA could function as a feedback loop, given that T3 decreases hepatic cholesterol levels.

scholarly journals Calcium-Activated Potassium Channels and the Regulation of Vascular Tone

Physiology ◽  
2006 ◽  
Vol 21 (1) ◽  
pp. 69-78 ◽  
Author(s):  
Jonathan Ledoux ◽  
Matthias E. Werner ◽  
Joseph E. Brayden ◽  
Mark T. Nelson
Keyword(s):  
Smooth Muscle ◽  
Potassium Channels ◽  
Vascular Function ◽  
Vascular Tone ◽  
Calcium Signals ◽  
Different Types ◽  
Calcium Activated Potassium Channels ◽  
Regulation Of Vascular Tone

Different calcium signals in the endothelium and smooth muscle target different types of Ca2+-sensitive K+ channels to modulate vascular function. These differential calcium signals and targets represent multilayered opportunities for prevention and/or treatment of vascular dysfunctions.

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