Retinoid X receptor alpha is a spatiotemporally predominant therapeutic target for anthracycline-induced cardiotoxicity
| Autor: | Alexey V. Dvornikov, Yong Wang, Qi Qiu, Xueying Lin, Tzung K. Hsiai, Xiaolei Xu, Yonghe Ding, Maengjo Kim, Zhang Hong, Yue Yu, Nadine Norton, Joerg Herrmann, Matthew R. Lowerison, Stephen C. Ekker, Xiao Ma, Ping Zhu, Zheng Wang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Cardiotonic Agents
Mutant 030204 cardiovascular system & hematology law.invention 03 medical and health sciences 0302 clinical medicine In vivo law Neoplasms Genetics Medicine Animals Humans Health and Medicine Isotretinoin Zebrafish Research Articles 030304 developmental biology Bexarotene 0303 health sciences Cardiotoxicity Multidisciplinary Retinoid X Receptor alpha Retinoid X receptor alpha biology business.industry Myocardium SciAdv r-articles Endothelial Cells Heart biology.organism_classification 3. Good health Disease Models Animal Cancer research Zonula Occludens-1 Protein Suppressor business Pericardium medicine.drug Research Article |
| Zdroj: | Science Advances |
| ISSN: | 2375-2548 |
| Popis: | RXRA is an endothelial- and early stage–predominant therapeutic target for treating anthracycline-induced cardiotoxicity. 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|