Abstract
The intracardiac synthesis of anthracycline alcohol metabolites by aldo-keto reductases (AKRs) contributes to the pathogenesis of anthracycline-related cardiotoxicity. AKR7A2 is the most abundant anthracycline reductase in hearts from donors with and without Down syndrome (DS), and its expression varies between individuals (≈tenfold). We investigated whether DNA methylation impacts AKR7A2 expression in hearts from donors with (n = 11) and without DS (n = 30). Linear models were used to test for associations between methylation status and cardiac AKR7A2 expression. In hearts from donors without DS, DNA methylation status at CpG site -865 correlated with AKR7A2 mRNA (Pearson's regression coefficient, r = -0.4051, P = 0.0264) and AKR7A2 protein expression (r = -0.5818, P = 0.0071). In heart tissue from donors with DS, DNA methylation status at CpG site -232 correlated with AKR7A2 protein expression (r = 0.8659, P = 0.0025). Multiple linear regression modeling revealed that methylation at several CpG sites is associated with the synthesis of cardiotoxic daunorubicinol. AKR7A2 methylation status in lymphoblastoid cell lines from donors with and without DS was examined to explore potential parallelisms between cardiac tissue and lymphoid cells. These results suggest that DNA methylation impacts AKR7A2 expression and the synthesis of cardiotoxic daunorubicinol.