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Journal Article
Research Support, N.I.H., Extramural
CPR: cardiac phosphatase in resuscitation.
Journal of Clinical Investigation 2023 May 2
Out-of-hospital cardiac arrest is associated with a dismal mortality rate and low long-term survival. A large pharmacological knowledge gap exists in identifying drugs that preserve neurological function and increase long-term survival after cardiac arrest. In this issue of the JCI, Li, Zhu, and colleagues report on their engineering of a 20-amino acid cell-permeable peptide (TAT-PHLPP9c) that antagonized the phosphatase PHLPP1 and prevented PHLPP1-mediated dephosphorylation and AKT inactivation. TAT-PHLPP9c administration maintained activated AKT after arrest and led to AKT-mediated beneficial effects on the heart, brain, and metabolism, resulting in increased cardiac output and cerebral blood flow and rescue of ATP levels in affected tissues. TAT-PHLPP9c improved neurological outcomes and increased survival after cardiac arrest in murine and porcine models of cardiac arrest. These findings provide proof of concept that pharmacological targeting of PHLPP1 may be a promising approach to augmenting long-term survival after cardiac arrest.
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