Background—
MicroRNAs (miRs) are small noncoding RNAs that posttranscriptionally control gene expression. Small-animal studies suggest that miRs might offer novel therapeutic targets in cardiovascular diseases such as cardioprotection of murine hearts after myocardial infarction via miR-92a inhibitors. Because the functional benefits of miR-92a inhibitors in larger preclinical 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 percutaneous ischemia/reperfusion (60 min/72 h or 7 days, respectively). Locked nucleic acid–modified antisense miR-92a (LNA-92a) was applied either regionally (antegrade or retrograde) with a catheter or systemically (intravenously). LNA-92a significantly (
P
<0.01) reduced miR-92a expression in the infarct zone regardless of the application venue. However, catheter-based delivery, but not intravenous infusion, of LNA-92a significantly (
P
<0.05) reduced the infarct size compared with control LNA–treated pigs, which correlated with an improved ejection fraction and left ventricular end-diastolic pressure (
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 and infarct size and postischemic loss of function. LNA-92a exerts cell-protective, proangiogenic, and anti-inflammatory effects. miR-92a inhibition might be a novel therapeutic tool to preserve cardiac function after ischemia.
Cardiac engineering of patches and tissues is a promising option to restore infarcted hearts, by seeding cardiac cells onto scaffolds and nurturing their growth in vitro. However, current patches fail to fully imitate the hierarchically aligned structure in the natural myocardium, the fast electrotonic propagation, and the subsequent synchronized contractions. Here, superaligned carbon-nanotube sheets (SA-CNTs) are explored to culture cardiomyocytes, mimicking the aligned structure and electrical-impulse transmission behavior of the natural myocardium. The SA-CNTs not only induce an elongated and aligned cell morphology of cultured cardiomyocytes, but also provide efficient extracellular signal-transmission pathways required for regular and synchronous cell contractions. Furthermore, the SA-CNTs can reduce the beat-to-beat and cell-to-cell dispersion in repolarization of cultured cells, which is essential for a normal beating rhythm, and potentially reduce the occurrence of arrhythmias. Finally, SA-CNT-based flexible one-piece electrodes demonstrate a multipoint pacing function. These combined high properties make SA-CNTs promising in applications in cardiac resynchronization therapy in patients with heart failure and following myocardial infarctions.
These results demonstrate that cardiovascular disease modulates the miR expression of BMCs in humans. Reducing the expression of the pro-apoptotic miR-34a improves the survival of BMCs in vitro and enhances the therapeutic benefit of cell therapy in mice after AMI.
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