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1. Heart failure (HF) can increase atrial fibrillation and induce cardiac hypermethylation. The homeobox genePitx2cplays important roles in the genesis of atrial fibrillation and the promoter region ofPitx2ccontains cytosine–phosphate–guanine islands. Therefore, epigenetic modification by hypermethylation may reduce Pitx2c expression in atrial myocytes. The aim of the present study were to evaluate whether HF can modulate DNA methylation ofPitx2cand the potential mechanisms involved.2. We used real-time polymerase chain reaction, immunoblotting and pyrosequencing to investigate RNA and protein expression, as well as the methylation ofPitx2c, in isoproterenol-induced HF, healthy rat left atria and in HL-1 cells with and without (control) exposure to angiotensin (Ang) II (0.1 and 1 μmol/L) or isoproterenol (1 or 10 μmol/L) for 24 h.3. The HF atrium exhibited increasedPitx2cpromoter methylation with increased DNA methyltransferase (DNMT) 1 and decreased Pitx2c protein levels compared with the normal atrium. Angiotensin II (0.1 and 1 μmol/L), increasedPitx2cpromoter methylation in HL-1 cells with increased DNMT1 and decreased Pitx2c and Kir2.1 protein levels compared with control cells. These effects were attenuated by the methylation inhibitor 5-aza-2′-deoxycytidine (0.1 μmol/L) and by the AngII receptor blocker losartan (10 μmol/L). However, isoproterenol (1 and 10 μmol/L) did not change the expression of the Pitx2c, DNMT1 and Kir2.1 proteins.4. In conclusion, HF inducesPitx2cpromoter hypermethylation and AngII may contribute to the hypermethylation in HF.