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Role of DNA Methylation on the Expression of the Anthracycline Metabolizing Enzyme AKR7A2 in Human Heart

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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.

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Acknowledgments

Research in this report was supported by the National Institute of General Medical Sciences and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under Awards R01GM073646 and R03HD076055. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, The State University of New York at Buffalo, 471 Kapoor Hall, Buffalo, NY, 14260, USA

    Carrie C. Hoefer, Adolfo Quiñones-Lombraña & Javier G. Blanco

  2. Department of Biostatistics, School of Public Health and Health Professions, The State University of New York at Buffalo, Buffalo, NY, 14260, USA

    Rachael Hageman Blair

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  1. Carrie C. Hoefer
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  2. Adolfo Quiñones-Lombraña
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Correspondence to Javier G. Blanco.

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Hoefer, C.C., Quiñones-Lombraña, A., Blair, R.H. et al. Role of DNA Methylation on the Expression of the Anthracycline Metabolizing Enzyme AKR7A2 in Human Heart. Cardiovasc Toxicol 16, 182–192 (2016). https://doi.org/10.1007/s12012-015-9327-x

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