miR-29a and miR-30c negatively regulate DNMT 3a in cardiac ischemic tissues: implications for cardiac remodelling

Recent evidences indicate that epigenetic changes play an important rolein the transcriptional reprogramming of gene expression that characterizescardiac hypertrophy and failure and may dictate response to therapy.Several data demonstrate that microRNAs (miRNAs) play critical rolesboth in normal cardiac function and under pathological conditions. Herewe assessed, in in vivo rat models of myocardial infarction (MI) andischemia-reperfusion (IR), the relationship between two miRNAs (miR-29aand miR-30c) and de novo methyltransferase (DNMT3a) which, alteringthe chromatin accessibility for transcription factors, deeply impacts geneexpression. We showed that the levels of members of miR-29 and miR30 families were down regulated in ischemic tissues whilst the proteinlevels of DNMT3a were increased, such a relation was not present inhealthy tissues. Furthermore, by an in vitro assay, we demonstrated thatboth miRNAs are able to down regulate DNMT3a by directly interactingwith DNMT3a 3’UTR and that miR-29a or miR-30c overexpression in thecardiac HL1 cell line causes decrease of DNMT3a enzyme both at themRNA and protein levels. Our data, besides confirming the down regulationof the miR-29a and miR-30c in infarcted tissues, envisage a cross-talkbetween microRNAs and chromatin modifying enzymes suggesting a newmechanism that might generate the alterations of DNA methylation oftenobserved in myocardial pathophysiology.