Abstract 16475: Sildenafil Modulates Myocardial Changes in Micro-RNA Profile Following Ischemia and Protects Mouse Hearts Against Ischemia-Reperfusion Injury
INTRODUCTION: Previous studies have shown that sildenafil causes changes in gene expression similar to these seen in ischemic preconditioning, therefore protects the heart against ischemia/reperfusion (I/R) injury. Since micro-RNA (miRNA) regulates gene expression, we hypothesized that: 1) I/R injury adversely disrupt normal miRNA expression leading to an increase in infarct size; and 2) sildenafil treatment reverse these changes in miRNA, thereby protect the heart against I/R injury.
METHODS: Mice were treated with PBS, I/R, or sildenafil (0.7mg/kg, i.p.) + I/R. Ischemia was induced by coronary artery occlusion for 30 min, followed by reperfusion for 30 min (for miRNA expression) or 24 h (for infarct size measurement using tetrazolium staining). miRNA microarray was used to gain an overall view of miRNA expression and q-PCR was used to confirm the microarray data.
RESULTS: Sildenafil (15.8±1.3%) attenuated the increase in infarct size observed in the I/R group (41.8±1.5%). Interestingly, I/R induced remarkable changes in miRNA profile compared to the PBS sham, thirty of these miRNA changes were reversed by Sildenafil treatment (only 9 shown in the Table, mean±SE, n=3, p<0.05). The reversal of these changes in the miRNAs, especially miRNA-17 for its role in attenuating inflammation, miRNA-499 for its anti-apoptotic effect, and miRNA-22 for preventing hypertrophy, may highlight important therapeutic targets and provide meaningful insight into the mechanism through which sildenafil induces cardioprotection.
CONCLUSION: Our results provide novel mechanistic information regarding cardioprotection with sildenafil by modulation of adverse changes in miRNA profile following I/R injury. More studies are needed to dissect the role of each of these miRNAs in cardioprotection with sildenafil or other phosphodiesterase-5 inhibitors.
- © 2011 by American Heart Association, Inc.