Branched-chain amino acid aminotransferase-1 regulates hypoxia/reoxygenation-associated cardiomyocyte ferroptosis via a nuclear factor erythroid 2-related factor-2 -dependent manner

  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.