Background: Aberrant DNA methylation at 5-cytosine (5-mC) contributes to maladaptive cardiac remodeling and heart failure (HF) progression induced by hemodynamic pressure overload and ischemic cardiac insults. However, no study has examined cardiac DNA methylation signatures upon exposure to hemodynamic volume overload despite being relatively common among HF patients.

Aim: To describe the landscape of DNA methylation in the context of hemodynamic volume overload.

Methods: Genome-wide approach was used to profile DNA methylation at early adaptive and late maladaptive cardiac remodeling in volume overloaded murine hearts following aortocaval shunt.

Results: The shunt mice exposed to short-term VO for 2 weeks exhibited beneficial cardiac remodeling as evidenced by preserved contractility that progressed to maladaptive cardiac remodeling with massive dilatation and impaired cardiac function upon long-term VO for 16 weeks. We found no loci-specific differentially methylated regions when comparing short-term VO versus corresponding sham. However, when comparing long-term VO versus corresponding sham, we identified 22 hyper-methylated loci, including 13 coding genes and 6 non-coding loci, and 6 hypo-methylated loci, including 2 coding genes and 3 non-coding loci. Loci-specific differentially methylated regions in Jph2, Ppp1r37, Vapb and Ipmk were validated using bisulfite sequencing PCR. Moreover, expression analyses of differentially methylated loci revealed a positive correlation with their corresponding gene expression levels of Nlrp5, Ets1, Spcs3, Rapgef6 and 2810007J24Rik, and a negative correlation with the gene expression levels of Jph2, Ppp1r37, Vapb, Ipmk and Rbbp7.

Conclusions: We identified novel differentially methylated genes in the remodeled heart exposed to hemodynamic VO, which would provide a new insight into the molecular pathogenesis of VO-induced pathological myocardial remodeling.