Inhibition of DNA methylation Reverses Aberrant Pathological Remodeling in the Setting of Pressure Overload
Authors: Russell‐Hallinan Adam , Neary Roisin , Watson Chris , Baugh John A. 
Published: June 2021

BackgroundHeart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome associated with significant morbidity and mortality. HFpEF is driven by pathological remodeling in the heart where there is hypertrophy of cardiomyocytes (cardiac hypertrophy) and an increased accumulation of extracellular matrix proteins in the interstitium (fibrosis). Recent evidence suggests that epigenetic processes such as DNA methylation are involved in the pathogenesis of cardiac remodeling. Inhibition of DNA methylation may present a novel therapeutic avenue for the treatment of HFpEF.PurposeThis study investigated the therapeutic potential of the DNA methyltransferase (DNMT) inhibitor 5‐azacytidine (5aza) to reverse established pathological cardiac remodeling in the transaortic constriction (TAC) mouse model of pressure overload.MethodsWild type C57Bl6/J mice underwent surgical constriction of the aortic arch. Sham surgery was used as the surgical control group. Mice began treatment four weeks post‐surgery with intraperitoneal administration of either placebo or 5aza every four days. Cardiac structure and function was examined in vivo using echocardiography. Gene expression of hypertrophic genes (Nppa and Myh7) and methyltransferase genes (DNMT1, DNMT3A and DNMT3B) was carried out by qPCR. Fibrotic deposition in the heart was assessed post‐mortem by picrosirius red staining for collagen.ResultsEchocardiographic analysis revealed that four weeks of 5aza treatment in mice with established cardiac hypertrophy resulted in a significant reduction in left ventricular (LV) mass (60.49 ± 3.83 vs. 47.21 ± 7.46 mg/cm, p<0.01), interventricular septal wall (1.15 ± 0.17 vs. 0.87 ± 0.08 mm, p<0.01) and LV posterior wall thickness (1.06 ± 0.15 vs. 0.89 ± 0.11 mm, p<0.05) compared to the placebo‐treated group. Reversal of cardiac hypertrophy by 5aza was also seen on the gene level with a reduction in Nppa and Myh7 expression. Collagen deposition was observed in both the interstitial and perivascular regions in TAC mice whereas collagen positivity was reduced and localized mostly around the blood vessels in the 5aza‐treated mice, comparable to that of the Sham group. Significant improvements in isovolumetric relaxation time (Placebo; 24.34 ± 3.085 vs. 5aza; 18.90 ± 4.44 ms, p<0.05) and E/A ratio (Placebo; 1.43 ± 0.23 vs. 5aza 1.91 ± 0.29, p<0.05) were demonstrated after treatment with 5aza. Interestingly, gene expression of DNMT1 and DNMT3B were significantly augmented in pressure overload but subsequently reversed with 5aza treatment.ConclusionTherapeutic options for HFpEF patients are limited. The DNA methylation inhibitor, 5aza, shows therapeutic potential by reversing established pathological cardiac remodeling with subsequent improvements in diastolic dysfunction and restoration of normal DNMT gene expression.Support or Funding InformationThis work was financially supported by UCD School of Medicine and Enterprise Ireland.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.