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Repurposing From Oncology to Cardiology: Low-Dose 5-Azacytidine Attenuates Pathological Cardiac Remodeling in Response to Pressure Overload Injury.

Abstract：

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:C57Bl6/J mice underwent surgical constriction of the aortic arch for 8 weeks. Mice began treatment 4 weeks post-surgery with either vehicle or 5aza (5 mg/kg). Cardiac structure and function was examined in vivo 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.

journal_name

J Cardiovasc Pharmacol Ther

journal_title

Journal of cardiovascular pharmacology and therapeutics

authors

Russell-Hallinan A,Neary R,Watson CJ,Baugh JA

doi

10.1177/1074248420979235

subject

Has Abstract

pub_date

2020-12-02 00:00:00

pages

1074248420979235

eissn

1074-2484

issn

1940-4034

pub_type

杂志文章

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Repurposing From Oncology to Cardiology: Low-Dose 5-Azacytidine Attenuates Pathological Cardiac Remodeling in Response to Pressure Overload Injury.