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Heart failure and angiotensin II modulate atrial Pitx2c promotor methylation
Author(s) -
Kao YuHsun,
Chen YaoChang,
Chung ChenChih,
Lien GiShih,
Chen ShihAnn,
Kuo ChingChuan,
Chen YiJen
Publication year - 2013
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12089
Subject(s) - methylation , dna methylation , promoter , chemistry , epigenetics , microbiology and biotechnology , medicine , angiotensin ii , endocrinology , gene expression , gene , receptor , biology , biochemistry
Summary Heart failure ( HF ) can increase atrial fibrillation and induce cardiac hypermethylation. The homeobox gene Pitx2c plays important roles in the genesis of atrial fibrillation and the promoter region of Pitx2c contains 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 of Pitx2c and the potential mechanisms involved. We used real‐time polymerase chain reaction, immunoblotting and pyrosequencing to investigate RNA and protein expression, as well as the methylation of Pitx2c , 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. The HF atrium exhibited increased Pitx2c promoter 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), increased Pitx2c promoter methylation in HL ‐1 cells with increased DNMT 1 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 Ang II receptor blocker losartan (10 μmol/L). However, isoproterenol (1 and 10 μmol/L) did not change the expression of the Pitx2c, DNMT 1 and Kir2.1 proteins. In conclusion, HF induces Pitx2c promoter hypermethylation and Ang II may contribute to the hypermethylation in HF .