Administration of low-dose 5-azacytidine attenuated pressure overload-induced pathological cardiac remodeling, myocardial hypertrophy, fibrosis, and diastolic dysfunction.
Does low-dose 5-azacytidine attenuate pathological cardiac remodeling and diastolic dysfunction in response to pressure overload injury?
Low-dose 5-azacytidine attenuates pressure overload-induced cardiac hypertrophy, fibrosis, and diastolic dysfunction by reducing DNA methylation.
INTRODUCTION: Recent evidence suggests that transcriptional reprogramming is involved in the pathogenesis of cardiac remodeling (cardiomyocyte hypertrophy and fibrosis) and the development of heart failure. 5-Azacytidine (5aza), an inhibitor of DNA methylation approved for hematological malignancies, has previously demonstrated beneficial effects on cardiac remodeling in hypertension. The aim of our work was to investigate whether pressure overload is associated with alterations in DNA methylation and if intervention with low-dose 5aza can attenuate the associated pathological changes. METHODS AND RESULTS: using echocardiography followed by post mortem histological assessment of hypertrophy and fibrosis. Global DNA methylation was examined by immunostaining for 5-methylcytosine (5MeC) and assessment of DNA methyltransferase expression. The results highlighted that pressure overload-induced pathological cardiac remodeling is associated with increased DNA methylation (elevated cardiac 5MeC positivity and Dnmt1 expression). Administration of 5aza attenuated pathological remodeling and diastolic dysfunction. These beneficial changes were mirrored by a treatment-related reduction in global 5MeC levels and expression of Dnmt1 and Dnmt3B in the heart. CONCLUSION: DNA methylation plays an important role in the pathogenesis of pressure overload-induced cardiac remodeling. Therapeutic intervention with 5aza, at a dose 5 times lower than clinically given for oncology treatment, attenuated myocardial hypertrophy and fibrosis. Our work supports the rationale for its potential use in cardiac pathologies associated with aberrant cardiac wound healing.
Russell‐Hallinan et al. (Wed,) conducted a other in Pressure overload-induced pathological cardiac remodeling. Low-dose 5-Azacytidine (5aza) was evaluated on Pathological cardiac remodeling (hypertrophy and fibrosis) and diastolic dysfunction. Administration of low-dose 5-azacytidine attenuated pressure overload-induced pathological cardiac remodeling, myocardial hypertrophy, fibrosis, and diastolic dysfunction.
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