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- W2301409700 abstract "Introduction: Recent work shows that mouse cardiac arrest and heart cell ischemia cause PI3K-Akt deactivation, while cardioprotective cooling appears mediated by Akt. To further test the role of PI3K-Akt during ischemic arrest/resuscitation, we developed novel TAT-p85 fusion proteins designed to enter cells rapidly to modulate Akt activation. p85 can both activate Akt via p110 binding, and via feedback deactivate Akt by PTEN binding. We hypothesized that TAT fused p85 lacking the PTEN binding site (TAT-Delta PTEN p85) would enhance p-Akt cardioprotection. Conversely, TAT fused p85 lacking the p110 binding site (TAT-delta p110p85) would decrease p-Akt and abrogate protection. Methods: A TAT-delta p110 p85 plasmid was constructed by deletion of nucleotides encoding amino acids 478-513. The TAT-delta PTEN p85 plasmid deleted amino acids 1-313. A TAT-GFP plasmid produced fluorescence-tagged TAT protein for measuring cell penetration kinetics. TAT proteins were expressed in E. Coli and purified. Cardiomyocytes were isolated from C57BL6/J mice and exposed to up to 90 min ischemic arrest with 3 h reperfusion (I/R). Cell viability was evaluated by propidium iodide uptake and p-Akt was measured by Western blot. PTEN activity was measured by Malachite green assay using PIP3 as substrate. Results: Western blot analysis demonstrated that TAT-delta p110 p85 could be transduced into cardiomyocytes within 5 min and levels maintained for more than 2h. TAT-delta p110 p85 blocked H2O2 induced p-Akt at both S473 and T308 sites in a dose-dependent fashion, while PTEN inhibition using TAT-delta PTEN p85 increased p-Akt. During cardiac cell ischemic arrest, p-Akt decreased within 30 min of arrest time. PTEN activity during ischemia increased 2-fold from baseline and was inversely correlated with Akt phosphorylation during I/R. TAT-delta p110 p85 increased cell death from 44.6 +/- 2.7% to 92.5 +/- 3.4%, while TAT-delta PTEN p85 decreased cell death caused by I/R in a concentration-dependent manner from 47.8 +/- 1.4% to 11.9 +/- 5.3%. Conclusions: We conclude that TAT-delta PTEN p85 with resulting PTEN inhibition may be a promising strategy to mimic and enhance protective cooling by more rapidly reactivating cellular Akt during heart ischemic arrest and resuscitation." @default.
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- W2301409700 date "2012-11-20" @default.
- W2301409700 modified "2023-09-25" @default.
- W2301409700 title "Abstract 297: Modulation of Ischemia-Resuscitation Injury by TAT-Mediated PTEN Inhibitors" @default.
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