DNA methylation inhibition attenuates pressure overload-induced cardiac hypertrophy in rats

Inhibitors of DNA methyl transferase (DNMT) might be useful for treating cardiac hypertrophy by preventing de novo methylation and reduced transcription of anti-hypertrophic genes. This approach had been tested, but without a detailed phenotypic and methylation analysis. Here, we subjected rats to pressure overload and treatment with the DNMT inhibitor N-phthalyl-L-tryptophan (RG108) and analysed DNA methylation by cardiomyocyte (CM)-specific reduced representation bisulphite sequencing (RRBS). Rats were divided into 4 groups of n=12-16 each, subjected to sham or clip-based TAC surgery and treated daily with the non-nucleosidic, non-isoform specific DNMT inhibitor RG108 or solvent only. 4 weeks later, rats received cardiac MRI; heart weight and gene expression (qPCR) were quantified. For DNA methylation analysis, CM nuclei were isolated by magnetic cell separation with an antibody against PCM1, DNA was subjected to RRBS and data was analysed using R and IPA software (n=4 per group).