Abstract 16397: Cardiac Deletion of Dicer Protects Against Acute Myocardial Ischemia-Reperfusion Injury
Objective: MicroRNAs (miRNA) are small, endogenous, conserved, noncoding RNAs that down-regulate protein production by translational repression. Dicer, a RNase III endonuclease essential for microRNA processing, has a major impact on cardiac development and remodeling, but little is known about the postnatal role of Dicer in myocardial ischemia-reperfusion injury (I/R).
Methods and Results: We established a transgenic mouse model with cardiac-specific deletion of Dicer by crossing Dicer flox/flox (F/F) mice with myh6-MerCreMer (MCM) via tamoxifen dependent Cre-loxP mediated DNA recombination. Two weeks after tamoxifen induced Dicer inactivation, no significant differences in histology or heart function were observed between tamoxifen and control animals despite a global downregulation of microRNAs in the heart. However, in response to 45min ischemia by LAD ligation followed by 24hrs reperfusion in vivo, cardiac Dicer inactivation resulted in reduced I/R injury, and TTC and phthalocyanine blue staining revealed significantly smaller infarct size as compared with control (26%±9%, n=9 vs. 56%±17%, n=6, P<0.05). Consistent with reduced infarct size, cardiac Dicer inactivation led to reduced cardiomyocyte apoptosis after I/R injury, as identified by TUNEL staining. Furthermore, cleaved caspase 3 levels were reduced in Dicer inactivated hearts. Cytokine array analysis showed reduced expression of inflammatory cytokines, including IFN-gama, and TNF-alpha, following ischemia-reperfusion.
Conclusions: We conclude that cardiac deletion of Dicer protects against ischemia-reperfusion injury by inhibiting apoptotic signaling and inflammation.
- © 2011 by American Heart Association, Inc.