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

Xiao Ma, Ping Zhu, Yonghe Ding, Hong Zhang, Qi Qiu, Alexey V. Dvornikov, Zheng Wang, Maengjo Kim, Yong Wang, Matthew Lowerison, Yue Yu, Nadine Norton, Joerg Herrmann, Stephen C. Ekker, Tzung K. Hsiai, Xueying Lin, Xiaolei Xu

Research output: Contribution to journalArticle

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 spatiallyand 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.

Original languageEnglish (US)
Article numbereaay2939
JournalScience Advances
Volume6
Issue number5
DOIs
StatePublished - Jan 29 2020

ASJC Scopus subject areas

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    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(5), [eaay2939]. https://doi.org/10.1126/sciadv.aay2939