PUBLICATION
Retinoid X receptor alpha is a spatiotemporally predominant therapeutic target for anthracycline-induced cardiotoxicity
- Authors
- Ma, X., Zhu, P., Ding, Y., Zhang, H., Qiu, Q., Dvornikov, A.V., Wang, Z., Kim, M., Wang, Y., Lowerison, M., Yu, Y., Norton, N., Herrmann, J., Ekker, S.C., Hsiai, T.K., Lin, X., Xu, X.
- ID
- ZDB-PUB-200221-17
- Date
- 2020
- Source
- Science advances 6: eaay2939 (Journal)
- Registered Authors
- Ding, Yonghe, Ekker, Stephen C., Lin, Xueying, Ma, Xiao, Xu, Xiaolei, Zhu, Ping
- Keywords
- none
- MeSH Terms
-
- Myocardium/metabolism
- Myocardium/pathology
- Cardiotonic Agents/pharmacology
- Zebrafish
- Endothelial Cells/drug effects
- Endothelial Cells/metabolism
- Bexarotene/pharmacology
- Isotretinoin/pharmacology
- Neoplasms/complications
- Neoplasms/drug therapy
- Animals
- Disease Models, Animal
- Heart/drug effects*
- Heart/physiopathology
- Zonula Occludens-1 Protein/genetics*
- Cardiotoxicity/drug therapy*
- Cardiotoxicity/etiology
- Cardiotoxicity/genetics
- Retinoid X Receptor alpha/agonists
- Retinoid X Receptor alpha/genetics*
- Pericardium/drug effects
- Humans
- PubMed
- 32064346 Full text @ Sci Adv
Citation
Ma, X., Zhu, P., Ding, Y., Zhang, H., Qiu, Q., Dvornikov, A.V., Wang, Z., Kim, M., Wang, Y., Lowerison, M., Yu, Y., Norton, N., Herrmann, J., Ekker, S.C., Hsiai, T.K., Lin, X., Xu, X. (2020) Retinoid X receptor alpha is a spatiotemporally predominant therapeutic target for anthracycline-induced cardiotoxicity. Science advances. 6:eaay2939.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping