MicroRNA-31 promotes adverse cardiac remodeling and dysfunction in ischemic heart disease

•Here, we present microRNA-31 (miR-31) as a novel potential therapeutic target for post-ischemic heart failure.•We identified a progressive time-dependent cardiac up-regulation of miR-31 following myocardial infarction (MI).•Hypoxia and oxidative stress also induce the increase of miR-31 expression in cardiac cell cultures.•We found that miR-31 modulates genes that may be relevant to cardiac function and structure such as Tnnt2, E2F6, Nr3c2, and Timp4.•In vivo miR-31 inhibition after MI led to de-repression of its target genes, attenuated infarct size and ameliorated cardiac dysfunction in rats.•Additional preclinical studies are necessary for the full development of mir-31 inhibition as a novel therapeutic for post-MI heart failure.

RationaleMyocardial infarction (MI) triggers a dynamic microRNA response with the potential of yielding therapeutic targets.ObjectiveWe aimed to identify novel aberrantly expressed cardiac microRNAs post-MI with potential roles in adverse remodeling in a rat model, and to provide post-ischemic therapeutic inhibition of a candidate pathological microRNA in vivo.Methods and resultsFollowing microRNA array profiling in rat hearts 2 and 14 days post-MI, we identified a time-dependent up-regulation of miR-31 compared to sham-operated rats. A progressive increase of miR-31 (up to 91.4 ± 11.3 fold) was detected in the infarcted myocardium by quantitative real-time PCR. Following target prediction analysis, reporter gene assays confirmed that miR-31 targets the 3´UTR of cardiac troponin-T (Tnnt2), E2F transcription factor 6 (E2f6), mineralocorticoid receptor (Nr3c2) and metalloproteinase inhibitor 4 (Timp4) mRNAs. In vitro, hypoxia and oxidative stress up-regulated miR-31 and suppressed target genes in cardiac cell cultures, whereas LNA-based oligonucleotide inhibition of miR-31 (miR-31i) reversed its repressive effect on target mRNAs. Therapeutic post-ischemic administration of miR-31i in rats silenced cardiac miR-31 and enhanced expression of target genes, while preserving cardiac structure and function at 2 and 4 weeks post-MI. Left ventricular ejection fraction (EF) improved by 10% (from day 2 to 30 post-MI) in miR-31i-treated rats, whereas controls receiving scrambled LNA inhibitor or placebo incurred a 17% deterioration in EF. miR-31i decreased end-diastolic pressure and infarct size; attenuated interstitial fibrosis in the remote myocardium and enhanced cardiac output.ConclusionmiR-31 induction after MI is deleterious to cardiac function while its therapeutic inhibition in vivo ameliorates cardiac dysfunction and prevents the development of post-ischemic adverse remodeling.