DOI: 10.1101/490706Dec 8, 2018Paper

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

BioRxiv : the Preprint Server for Biology
Xiao MaXiaolei Xu

Abstract

While 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 RX...Continue Reading

Related Concepts

Doxorubicin
Gene Activation
Genes
Isotretinoin
Myocardium
Retinoids
Vertebrates
Zebrafish
Mutagenesis Process
Retinoid X Receptor alpha

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