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.

5-Aza-2′-Deoxycytidine (5-Aza-dC, Decitabine) Inhibits Collagen Type I and III Expression in TGF-β1-Treated Equine Endometrial Fibroblasts

“…The same results were observed in human cardiac fibroblasts [ 59 ]. Our data also agree with other studies on humans, where it was observed that 5-aza-dC mitigates renal [ 68 , 71 ], cardiac [ 59 , 72 ], and pulmonary [ 60 , 73 , 74 ] fibrosis by reducing hypermethylation of genes associated with fibroblast activation. In another study, it was found that hypermethylation contributes to renal fibrosis and inhibition of DNMTs suppresses chronic unilateral ureteral obstruction-induced renal fibrosis [ 17 ].…”

The roles and mechanisms of epigenetic regulation in pathological myocardial remodeling

“…The supplementation of selenium which is an essential trace element showed obvious cardioprotective effects toward advanced glycation end products (AGEs)-induced heart failure via inhibiting DNMT2-induced DNA methylation of glutathione peroxidase 1 (GPX1) gene promoter in myocytes (165). Moreover, as an inhibitor of DNA methylation, 5-Azacytidine (5aza) has been shown to be effective in attenuating pressure overload-induced myocardial remodeling (166).…”

Targeting Epigenetic Regulation of Cardiomyocytes through Development for Therapeutic Cardiac Regeneration after Heart Failure

“…These “epidrugs” would potentially interfere with various epigenetic mechanisms to enhance regenerative cardiomyocytes or inhibit the negative response to cardiac injury [ 97 ]. It has even been suggested that some standard hypertensive drugs could play a major role in indirect epigenetic regulation [ 98 ]. Finally, the reconfiguration of mCpG regions has been suggested as a more individualized approach to cardiovascular-based therapies via epigenetic regulation [ 99 ].…”