Abstract 19722: Cardiac Deletion of miRNA-17-92 Cluster Augments Acute Myocardial Ischemia-Reperfusion Injury
Objective: MicroRNAs (miRNA) are small, endogenous, conserved, noncoding RNAs that down-regulate protein production by translational repression. The miR-17-92 cluster (encoding miR-17, -18a, -19a/b, -20a, and miR-92a) is highly expressed in stem cells and is up-regulated by ischemia, but little is known about the postnatal role of miR-17-92 in myocardial ischemia-reperfusion injury (I/R).
Methods and Results: We established a transgenic mouse model with cardiac-specific deletion of miR-17-92 by crossing miR-17-92 flox/flox (F/F) mice with myh6-MerCreMer (MCM) via tamoxifen dependent Cre-loxP mediated DNA recombination. Two weeks after tamoxifen induced miRNA-17-92 inactivation, no significant differences in histology were observed between tamoxifen and corn oil treated animals despite downregulation of miR-17, -18a, -19a/b, -20a, and miR-92a in the heart. However, in response to 45min ischemia by LAD ligation followed by 24hrs reperfusion in vivo, cardiac miR-17-92 knockout resulted in increased I/R injury, and TTC and phthalocyanine blue staining revealed significantly larger infarct size as compared with control (63.6%±3.9%, n=10 vs. 41.0%±3.1%, n=7, P<0.05). Consistent with increased infarct size, cardiac miR-17-92 inactivation led to increased cardiomyocyte apoptosis after I/R injury, as identified by TUNEL staining. Furthermore, PTEN levels were increased while Phospho-Akt levels were significantly decreased in miR-17-92 inactivated hearts.
Conclusions: We conclude that cardiac deletion of miR-17-92 augments the ischemia-reperfusion injury by inhibiting survival signaling. .
- © 2012 by American Heart Association, Inc.