Abstract:
AIM To investigate the role and mechanism of branched-chain amino acid aminotransferase 1 (BCAT1) in regulating cardiomyocyte ferroptosis and hypoxia/reoxygenation injury.
METHODS Neonatal rat ventricular myocytes (NRVMs) were routinely isolated from neonatal Sprague-Dawley rats and were in vitro cultured. NRVMs were transfected with adenovirus vectors over-expressing or silencing BCAT1 and then were subjected to hypoxia/reoxygenation (H/R) or the ferroptosis inducer, Erastin. ML385, a specific inhibitor of nuclear factor E2-related factor-2 (NRF2), was administered into NRVMs to explore the involvement of NRF2 in cardiomyocyte ferroptosis regulated by BCAT1.
RESULTS BCAT1 silencing exacerbated H/R-induced NRVM death, a phenomenon basically eliminated by the ferroptosis inhibitor Ferr-1. Over-expression of BCAT1 significantly ameliorated H/R-induced cell death and Erastin-induced ferroptosis. BCAT1 over-expression significantly increased the protein abundance of NRF2 and up-regulated the mRNA levels of NRF2 downstream gene Ho-1, Nqo-1 and Trx-1. Inhibition of NRF2 by ML385 blocked the protective effect of BCAT1 over-expression against H/R injury and ferroptosis (all P<0.05).
CONCLUSION BCAT1 regulates cardiomyocyte ferroptosis via a NRF2-dependent manner, which might be a key mechanism of BCAT1’s effect on H/R-induced cardiomyocyte injury.
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