Abstract 15246: Influence of Genetic Deletion of MicroRNA-92a on Embryonic Development and Recovery After Acute Myocardial Infarction
MicroRNAs (miRs) are small noncoding RNA molecules which bind to mRNAs of their target genes, thereby regulating gene expression on the posttranscriptional level. The miR-17~92 cluster has a crucial function during embryonic development and the individual cluster members regulate angiogenesis. Mice deficient for the miR-17~92 cluster show severe cardiac and pulmonary defects. A pharmacological inhibition of miR-92a improved postnatal neovascularization after ischemia. The relevance of the specific genetic depletion of miR-92a during embryonic development and postnatal angiogenesis is so far unknown. Therefore, we characterized miR-92a knockout mice. The expression of miR-92a was completely deleted in miR-92a-/- mice. MiR-92a-/- mice are viable and fertile, however, miR-92a-/- mice from heterozygous crosses are recovered at less than the predicted Mendelian ratio (observed: 16% vs. expected: 25%, p<0.05). Furthermore, female and male miR-92a-/- mice show a decreased body weight in comparison to wild type (WT) (-3.4±0.5g (p<0.05) and -3.7±0.4g (p<0.05), respectively) during the observation period from 4.5 to 7.5 weeks of age. Since the pharmacological inhibition of miR-92a improved the recovery after ischemia, we investigated whether miR-92a-/- mice exhibit an improved cardiac function after inducing myocardial infarction (MI). Using high-resolution echocardiography, we observed that miR-92a-/- mice showed a significant reduction of myocardial wall motion abnormalities two weeks after MI (WMSI [[Unable to Display Character: ∆]]day14-day0; WT: 0.226±0.075; miR-92a-/-: 0.042±0.060; p<0.05) indicating an improved myocardial function compared to WT. Consistently, infarct size (-27.86 ±8.12% vs. WT, p<0.05) and fibrosis (-27.50±12.49% vs. WT) were reduced in miR-92a-/- compared to WT mice. In summary, we show that genetic depletion of miR-92a affects embryonic development in a low penetrance manner. The majority of miR-92a-/- mice is born with no obvious basal phenotype except for a lower body weight. Adult miR-92a-/- mice showed an improved recovery after MI, which is consistent with previous studies with pharmacological inhibitors. Ongoing studies address the involvement of specific cell lineages in Cre-deleter lines.
- © 2012 by American Heart Association, Inc.