Abstract 15560: Inhibition of the Microrna Let-7 Enhances Epithelial-Mesenchymal Transition and Recruitment of Epicardial Cells After Acute Myocardial Infarction
Intrinsic regeneration of the myocardium after acute myocardial infarction (AMI) is limited. The miRNA let-7 is involved in epithelial-mesenchymal transition (EMT) as well as differentiation processes and is upregulated after myocardial infarction. To elucidate the role of let-7 in myocardial regeneration let-7 family members were inhibited by locked-nucleid acid antimiRs (LNA-let7, 20 mg/kg sc.). Administration at day (d)0 and d2 post-AMI resulted in a substantial knockdown of let-7 family members up to d28. Inhibition of let-7 prevented worsening of left ventricular ejection fraction (EF) and improved wall motion score index (WMSI) compared to control LNAs (delta EF vs. d0 0.13±2.2% vs.-9.7±2.4%, p<0.01; delta WMSI vs. d0 -8.9±4.7% vs. 21±6.1% p<0.01). There were no differences in infarct size and capillary density suggesting that LNA-let7 does not interfere with early cardiac cell death or angiogenesis. However, expression of the EMT marker vimentin and of smMHC was significantly elevated in the border zone (p=0.02, respectively), indicating increased EMT after inhibition of let-7 that may beneficially affect scar remodeling. Indeed, there was a trend to a higher expression of the direct let-7 targets and positive EMT-regulators lin-28 and HMGA2 (1.3-fold, respectively) and HMGA2+ cells were increased in the infarcted area after LNA-let7 treatment (2.1-fold). In addition, TCF21+ epicardial cells were profoundly increased in the LNA-let7 group (2.8-fold, p<0.01) and expression of epicardial markers such as WT1 tended to be higher (1.4-fold) indicative for an activation of the epicardium by inhibition of let-7. Finally, E-cadherin, which is enriched in epicardial cells, was also significantly increased (p=0.02).
In conclusion, let-7 is upregulated after AMI and inhibition of let-7 leads to sustained improvement of cardiac functions. The improvement is associated with increased EMT and enhanced activation of epicardial cells beneficially affecting repair and remodeling processes after AMI.
- © 2013 by American Heart Association, Inc.