Hypermethylation of Hif3a and Ifltd1 Is Associated with Atrial Remodeling in Pressure- overload Murine Model

Atrial remodeling is one of major pathophysiological mechanisms of atrial fibrillation (AF). Atrial remodeling progresses based on aging, background diseases including hypertension and heart failure, and AF itself. However, its mechanism and reversibility have not been completely elucidated. In this study, we focused on the involvement of DNA methylation in atrial remodeling. Mice underwent transverse aortic constriction (TAC) procedure to generate pressure overload model. After 14 days, TAC-operated mice showed a significant increase in atrium/body weight ratio and deposition of collagen fiber in atria. Comprehensive analysis of RNA-Sequencing (RNA-Seq) and Methyl-CpG-Binding Domain Sequencing (MBD-Seq) in left atrial tissue identified Hif3a and Ifltd1 showing increased DNA methylation in their promoter regions and decreased RNA expression. We also performed transient pressure overload model by removing aortic constriction at 3 or 7 days after initial TAC procedure (R3 or R7 groups). The reduction of RNA expression was achieved at R3 for Hif3a, and in R7 for Ifltd1. The heterozygous Dnmt1 gene targeting mouse (Dnmt1 ^mut ) showed disappearance of the reduction in RNA expression and increase in atrium/body weight ratio. DNA methylation was thought to contribute to at least part of the atrial remodeling in the pressure overload mouse model.