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

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.

Untangling the Cooperative Role of Nuclear Receptors in Cardiovascular Physiology and Disease

“…The protective action of bexarotene through LKB1/p70S6K is also conserved in spontaneously hypertensive rats (SHR), where it significantly reduces left ventricular hypertrophy without affecting blood pressure [107]. The cardioprotective action of the rexinoids isotretinoin and bexarotene was highlighted in a recent study showing that activation of endothelial RXRα protects against anthracycline-induced cytotoxicity in zebrafish [108].…”

Building the vertebrate codex using the gene breaking protein trap library

“…At the end of this pipeline, 204 GBT-candidate lines met the highest stringency of confirmed expression linkage and were classified as ‘GBT-confirmed lines’ ( Figure 2A ). While 57 of these GBT-confirmed lines have been previously published ( Clark et al, 2011a ; Ding et al, 2013 ; Ding et al, 2017 ; El-Rass et al, 2017 ; Ma et al, 2020 ; Westcot et al, 2015 ), 147 of these GBT-confirmed lines are newly characterized in this manuscript and were selected for confirmation based upon their expression pattern and/or homozygous phenotype ( Supplementary file 1 ). A small subset of these GBT-confirmed lines mapped to areas in the genome without annotated transcripts.…”

Modeling Inherited Cardiomyopathies in Adult Zebrafish for Precision Medicine

“…Whereas the former type identifies susceptibility genes, the latter type could suggest therapeutic target genes. As shown by studies of GBT419/rxraa, Ma et al (2020) established retinoid X receptor alpha a (rxraa) as a new therapeutic target gene for DIC and reported the underlying mechanism. Through leveraging the integrated loxP sites in the insertional vector, they uncovered a spatiotemporally predominant mechanism of rxraa-based therapy, i.e., that endothelial-specific rxraa activation, but not myocardial-or epicardial-rxraa activation, conferred therapeutic effects on DIC (Ma et al, 2020).…”

“…As shown by studies of GBT419/rxraa, Ma et al (2020) established retinoid X receptor alpha a (rxraa) as a new therapeutic target gene for DIC and reported the underlying mechanism. Through leveraging the integrated loxP sites in the insertional vector, they uncovered a spatiotemporally predominant mechanism of rxraa-based therapy, i.e., that endothelial-specific rxraa activation, but not myocardial-or epicardial-rxraa activation, conferred therapeutic effects on DIC (Ma et al, 2020). Besides identifying therapeutic target genes via harnessing salutary modifiers, mechanistic studies of deleterious modifiers could also identify a particular way to manipulate the modifier gene to exert therapeutic effects.…”