Abstract 18290: Mitochondrial-Targeted Overexpression of Transcriptionally Inactive STAT3 in the Heart Reduces Infarct Size and Improves Contractile Recovery Following Ischemia and Reperfusion
Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor that drives expression of antiapoptotic and antioxidant genes. STAT3 contributes a crucial role in protection against ischemia (ISC)-reperfusion (REP) injury. STAT3 is also found in the mitochondria, where it modulates the activity of the electron transport chain (ETC) and the permeability transition pore. We have previously shown that transgenic mice overexpressing mitochondrial-targeted, transcriptionally inactive STAT3 in cardiomyocytes (MLS-STAT3E mice) exhibit a persistent, partial blockade of electron transfer through complex I that uniquely does not lead to tissue dysfunction at baseline yet increases mitochondrial ischemic tolerance. MLS-STAT3E protects complex I against ischemic damage, attenuates reactive oxygen species (ROS) production from the ETC and inhibits cytochrome c release during ISC. The direct contribution of non-transcriptional, mitochondria-localized STAT3 to protection during ISC-REP remains to be established. We hypothesize that the enhanced mitochondrial tolerance seen in MLS-STAT3E mice will decrease cardiac injury during ISC-REP. In the isolated buffer-perfused heart model of ISC-REP, non-transgenic littermate (WT) hearts subjected to 35 min of ISC and 60 min of REP exhibit an infarct size of 34 ± 2% (n=10) of the left ventricle (LV) risk area. MLS-STAT3E hearts are more resistant to ISC-REP injury with a decreased infarct size (23 ± 5%; P<0.05, n=10). Contractile recovery, expressed as a percent of LV developed pressure before ISC, is improved in MLS-STAT3E mice compared to WT (10 ± 2% WT vs. 21 ± 3% MLS-STAT3E; P<0.05, n=10). Mitochondria isolated after ISC-REP show MLS-STAT3E-mediated attenuation of ROS release. These results suggest that the partial and persistent blockade of complex I present in MLS-STAT3E decreases ISC-REP injury. Our data implicates STAT3 as a mediator of cardioprotection not only via canonical action as a transcription factor, but also as a modulator of ETC activity directly in the mitochondria.
- © 2013 by American Heart Association, Inc.