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<0.01), decreased cardiomyocyte apoptosis (TUNEL 17.1±14.6 vs 44.3±8.4, p=0.02) and oxidative stress (DHE 18.7±7.5 vs 31.1±5.6, p=0.03), improved mitochondrial function and myocardial energetics, and reduced infarct size (TTC 29.7±2.6 vs 35.5±2.7, p=0.02). In long-term porcine I-R experiments evaluated with MRI and 3D-echo, PTEN inhibition increased myocardial salvage (29.8±4.4 vs 7.1±3.8, p<0.01), reduced infarct size (LGE 28.3±1.7 vs 36.7±2.6, p=0.01), improved both systolic and diastolic function (EF 39.8±4.1 vs 34.5±3.7, p=0.02; -dP/dt -917±4.1 vs -505±49, p=0.01) and reduced adverse cardiac remodeling (LV mass 54.8±3.3 vs 68.3±2.5, p<0.05)
Conclusions: PTEN inhibition ameliorates I-R injury both using in vitro and in vivo (porcine) models via enhancing RISK pathway activation
Author Disclosures: C.G. Santos-Gallego: None. B. Picatoste: None. I.U. Njerve: None. K. Ishikawa: None. T.P. Vahl: None. J. Narula: None. J.J. Sanz: None. R.J. Hajjar: None. V. Fuster: None. J.J. Badimon: None.
- © 2016 by American Heart Association, Inc.