Abstract 18097: PTEN Inhibition With VO-OHPIC Ameliorates Myocardial Ischemia-Reperfusion Injury Mediated by RISK Pathway Activation-Mediated Reduction of Apoptosis: An in vitro and in vivo Study

Introduction: RISK is the main cardioprotective pathway against ischemia-reperfusion (I-R) injury, and starts with the phosphorylation (activation) of Akt. Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a primary phosphatase that dephosphorylates (deactivates) Akt Hypothesis: PTEN inhibition using the drug VO-OHPIC ameliorates I-R injury using both in vitro and porcine models Methods: Human AC16 cardiomyocytes underwent hypoxia-reoxygenation; PTEN inhibition was achieved genetically (siRNA) or pharmacologically (VO-OHPIC) in the presence or absence of inhibitors of the RISK and SAFE cardioprotective pathways. In vivo I-R was induced in pigs by 1-hour balloon occlusion of the proximal LAD; VO-OHPIC was administered IV 15 min pre-reperfusion. 10 pigs were sacrificed 1 day post-I-R to study mechanisms of cardioprotection. 12 additional pigs were studied with magnetic resonance (MRI) and 3D-echocardiography 1 week and 1 month post-I-R to assess the cardioprotection and LV remodeling Results: In vitro , both genetic and pharmacological PTEN inhibition activated RISK (but not SAFE) pathway, increased cell viability and reduced apoptosis (flow cytometry for annexin-V and caspase-3 activation). The benefits of PTEN inhibition were mediated via RISK activation because they were abrogated with RISK (but not SAFE) inhibitors. In short-term porcine experiments, PTEN inhibition activated RISK pathway (pAkt/Akt 0.78±0.12 vs 0.25±0.2, p Conclusions: PTEN inhibition ameliorates I-R injury both using in vitro and in vivo (porcine) models via enhancing RISK pathway activation