Abstract 12410: Inhibition of PARP1 Reduces Infarct Size and Attenuates Acute Left Ventricular Dilation in Mice After Myocardial Ischemia / Reperfusion Injury
Introduction: Activation of Poly ADP-ribose polymerase 1 (PARP1) contributes to tissue damage during ischemia/reperfusion (I/R) injury due to rapid depletion of NAD+ and ATP pools causing cellular dysfunction and death. We hypothesized that inhibiting PARP1 would not only reduce myocardial infarct (MI) size in mice, but that the reduced energy depletion might also help preserve LV geometry early after MI.
Methods and Results for Acute MI: Panel A) In the study of MI size, ~12 wk old C57BL/6 mice were subject to 30 min LAD occlusion followed by 120 min reperfusion. Risk region and infarct size were assessed by Phthalo blue and TTC staining. Treatment with a PARP1 inhibitor starting 5 min before reperfusion and continuing for 2 hr significantly reduced infarct size in a dose-dependent manner (p≤0.05 by ANOVA, n=8-9/group) compared to controls, reaching a 64% reduction at a dose of 3.6 μmol/kg, IP (plasma conc. ~200nM).
Methods and Results for Acute Pump Failure: Panel B) To test if PARP1 inhibition could protect against acute pump failure after MI, mice were first subject to 40 min LAD occlusion and 60 min reperfusion to obtain similar MI sizes, then treated with either vehicle or 3.6 μmol/kg PARP1 inhibitor over the next 2 hr (n=8/group). At 24 hr post reperfusion, left ventricular (LV) volumes were evaluated from base to apex with 2D echo (Vevo 2100). Risk region and MI size were quantified after imaging to confirm no significant difference in infarct size. Compared to control mice, delayed PARP1 inhibition significantly reduced both LV EDV (18.1%, p≤0.05) and LV ESV (24.1%, p≤0.05).
Conclusions: PARP1 inhibition initiated before and maintained during reperfusion reduces MI size. In the second study, we showed for the first time that delayed PARP1 inhibition attenuates acute LV dilation, independent of its ability to reduce MI size. Together, these findings suggest that PARP1 inhibition may prove beneficial in the settings of both acute MI and acute pump failure.
- © 2013 by American Heart Association, Inc.