scholarly journals Retinoid X receptor alpha is a spatiotemporally-specific therapeutic target for doxorubicin-induced cardiomyopathy in adult zebrafish

2018 ◽  
Author(s):  
Xiao Ma ◽  
Yonghe Ding ◽  
Hong Zhang ◽  
Qi Qiu ◽  
Alexey V. Dvornikov ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Late Phase ◽  
Retinoid X Receptor ◽  
Genetic Modifiers ◽  
Adult Zebrafish ◽  
Mutagenesis Screen ◽  
Receptor Alpha ◽  
Cardioprotective Effects ◽  
Retinoid X Receptor Alpha

AbstractWhile the genetic suppressor screen is efficient in suggesting therapeutic genes, this strategy has yet to be successful for cardiomyopathies in vertebrates. To develop such a strategy, we recently established a mutagenesis screen platform in zebrafish for systematic discovery of genetic modifiers of doxorubicin-induced cardiomyopathy (DIC). Here, we further revealed both molecular and cellular insights of the first salutary modifier emerged from the screen, i.e. gene-breaking transposon (GBT) 0419 that affects the retinoid X receptor alpha a (rxraa) gene. First, by rescuing the mutation in tissue-specific manner with multiple Cre-loxP systems, we demonstrated that the endothelial, but not myocardial or epicardial, function of rxraa is primary to this cardioprotective effects. Next, we showed that the rxraa-associated salutary effects on DIC were conferred partially by the activation of retinoid acid (RA) signaling. Finally, we identified isotretinoin and bexarotene, 2 US Food and Drug Administration-approved RXRA agonists that are effective in treating adult zebrafish DIC when administered during the early, but not the late, phase of DIC progression. Collectively, we provided the first in vivo genetic evidence in supporting RXRA as the therapeutic target for DIC, and uncovered a previously unrecognized spatiotemporally-restricted mechanism for this gene-based therapeutic strategy. Our study also justified that searching salutary modifiers via zebrafish mutagenesis screen can be effective in discovering new therapeutic targets for cardiomyopathies.

scholarly journals Retinoid X receptor alpha is a spatiotemporally predominant therapeutic target for anthracycline-induced cardiotoxicity

2020 ◽  
Vol 6 (5) ◽  
pp. eaay2939 ◽  
Author(s):  
Xiao Ma ◽  
Ping Zhu ◽  
Yonghe Ding ◽  
Hong Zhang ◽  
Qi Qiu ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Late Phase ◽  
Screening Strategy ◽  
Retinoid X Receptor ◽  
Therapeutic Effects ◽  
Receptor Alpha ◽  
Junction Protein ◽  
Cardioprotective Effects ◽  
Retinoid X Receptor Alpha

To uncover the genetic basis of anthracycline-induced cardiotoxicity (AIC), we recently established a genetic suppressor screening strategy in zebrafish. Here, we report the molecular and cellular nature of GBT0419, a salutary modifier mutant that affects retinoid x receptor alpha a (rxraa). We showed that endothelial, but not myocardial or epicardial, RXRA activation confers AIC protection. We then identified isotretinoin and bexarotene, two FDA-approved RXRA agonists, which exert cardioprotective effects. The therapeutic effects of these drugs only occur when administered during early, but not late, phase of AIC or as pretreatment. Mechanistically, these spatially- and temporally-predominant benefits of RXRA activation can be ascribed to repair of damaged endothelial cell-barrier via regulating tight-junction protein Zonula occludens-1. Together, our study provides the first in vivo genetic evidence supporting RXRA as the therapeutic target for AIC, and uncovers a previously unrecognized spatiotemporally-predominant mechanism that shall inform future translational efforts.

scholarly journals Glucocorticoids increase retinoid-X receptor alpha (RXRalpha) expression and enhance thyroid hormone action in primary cultured rat hepatocytes

1999 ◽  
Vol 22 (1) ◽  
pp. 81-90 ◽  
Author(s):  
S Yamaguchi ◽  
Y Murata ◽  
T Nagaya ◽  
Y Hayashi ◽  
S Ohmori ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Binding Protein ◽  
Rat Hepatocytes ◽  
Retinoid X Receptor ◽  
Type I ◽  
Receptor Alpha ◽  
Primary Cultured Rat Hepatocytes ◽  
Spot 14 ◽  
Cultured Rat Hepatocytes ◽  
Retinoid X Receptor Alpha

We have previously demonstrated that dexamethasone (DEX) enhances the T3-dependent increase in type I 5'-deiodinase (5'DI) mRNA in primary cultured rat hepatocytes grown as spheroids. Here we report that DEX-enhanced T3-responsiveness also occurs in two other T3-regulated hepatic genes, Spot 14 and malic enzyme. This enhancement was inhibited by pretreatment with cycloheximide and the stability of 5'DI and Spot 14 mRNAs was not affected by DEX. We thus hypothesized that a factor(s) that augments T3-responsiveness is induced by DEX. Among the possible candidates examined, retinoid-X receptor alpha (RXRalpha), which is a main heterodimer partner with T3 receptor, appeared to be involved. Whereas DEX increased the amount of RXRalpha mRNA, it did not affect the expression of other possible factors such as steroid receptor coactivator-1 and the binding protein of cAMP response element-binding protein. Northern and Western blot analysis, and electrophoretic mobility shift assay revealed that DEX increased RXRalpha expression at both the mRNA and protein levels. Maximal increase in RXRalpha protein was achieved with the addition of physiological concentrations of DEX (10(-8) M). To test whether the DEX-induced increase in RXRalpha affects ligand-dependent transcriptional activation through other receptors that form heterodimer with RXR, we examined its effect on the retinoic acid (RA)/RA receptor (RAR) system. Indeed, DEX also enhanced the RA-dependent increase in RARbeta mRNA in a cycloheximide-sensitive manner. Increase in the level of RXRalpha in hepatocytes by infection with the RXRalpha-expressing adenovirus resulted in enhancement of the T3-dependent increase in 5'DI mRNA. These results strongly suggest that the DEX-induced augmentation of T3-responsiveness in cultured hepatocytes is mediated, in part, by the increased expression of RXRalpha.

scholarly journals Stability of the Retinoid X Receptor-alpha Homodimer in the Presence and Absence of Rexinoid and Coactivator Peptide

2020 ◽  
Author(s):  
Zhengrong Yang ◽  
Donald D. Muccio ◽  
Nathalia Melo ◽  
Venkatram R. Atigadda ◽  
Matthew B. Renfrow
Keyword(s):  
Binding Pocket ◽  
Retinoid X Receptor ◽  
Heat Capacity Change ◽  
Scanning Calorimetry ◽  
Receptor Alpha ◽  
Average Value ◽  
A Value ◽  
Capacity Change ◽  
Differential Scanning Fluorimetry ◽  
Retinoid X Receptor Alpha

ABSTRACTDifferential scanning calorimetry and differential scanning fluorimetry were used to measure the thermal stability of human retinoid X receptor-alpha ligand binding domain (RXRα LBD) homodimer in the absence or presence of rexinoid and coactivator peptide, GRIP-1. The apo-RXRα LBD homodimer displayed a single thermal unfolding transition with a Tm of 58.7 °C and an unfolding enthalpy (ΔH) of 673 kJ/mol (12.5 J/g), much lower than average value (35 J/g) of small globular proteins. Using a heat capacity change (ΔCp) of 15 kJ/(mol·K) determined by measurements at different pH values, the free energy of unfolding (ΔG) of the native state was 33 kJ/mol at 37 °C. Rexinoid binding to the apo-homodimer increased Tm by 5 to 9 °C, and increased the ΔG of the native homodimer by 12 to 20 kJ/mol at 37 °C, consistent with the nanomolar dissociation constant (Kd) of the rexinoids. The increase in ΔG was the result of a more favorable entropic change due to interactions between the rexinoid and hydrophobic residues in the binding pocket, with the larger increases caused by rexinoids containing larger hydrophobic end groups. GRIP-1 binding to holo-homodimers containing rexinoid resulted in additional increases in ΔG of 14 kJ/mol, a value same for all three rexinoids. Binding of rexinoid and GRIP-1 resulted in a combined 50% increase in unfolding enthalpy, consistent with reduced structural fluidity and more compact folding observed in other published structural studies. Thermodynamic analysis thus provided a quantitative evaluation of the interactions between RXR and its agonist and coactivator.

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