Inhibition of MicroRNA-92a Protects Against Ischemia-Reperfusion Injury in a Large Animal Model
Background—MicroRNAs (miRs) are small non-coding RNAs that posttranscriptionally control gene expression. Small animal studies suggest that miRs might offer novel therapeutic targets in cardiovascular disease, such as cardioprotection of murine hearts after myocardial infarction via miR-92a inhibitors. Since the functional benefits of miR-92a inhibitors in larger pre-clinical models are not known, we assessed the therapeutic efficacy of miR-92a inhibition in a porcine model of ischemia and reperfusion.
Methods and Results—Pigs (n=5 per group) underwent percutaneus ischemia/reperfusion (60min/72h or 7 days, respectively). Locked nucleic acid-modified anti-sense miR-92a (LNA-92a) were applied either regionally (antegrade or retrograde) with a catheter or systemically (i.v.). LNA-92a significantly (p<0.01) reduced miR-92a expression in the infarct zone after LNA-92a administration regardless of the application venue. However, catheter-based delivery, but not i.v. infusion, of LNA-92a significantly (p<0.05) reduced the infarct size compared to control LNA treated pigs, which correlated with an improved ejection fraction and LVEDP (p<0.05). Histochemistry revealed that LNA-92a increased capillary density, but decreased leukocyte influx and cardiac cell death. Complete loss of miR-92a in mice attenuated the infarct-related myocardial dysfunction to a larger extent than cardiomyocyte-specific miR-92a deletion. In vitro, LNA-92a protected against hypoxia/reoxygenation-induced cardiomyocyte cell death.
Conclusions—Regional LNA-92a delivery reduces miR-92a levels as well as infarct size and post-ischemic loss of function. LNA-92a exerts cell-protective, pro-angiogenic and anti-inflammatory effects. miR-92a inhibition might be a novel therapeutic tool to preserve cardiac function after ischemia.
- Received February 11, 2013.
- Revision received June 30, 2013.
- Accepted July 12, 2013.