Division of Cardiology, Department of Medicine, David Geffen School of Medicine.
Cardiovascular Theme, David Geffen School of Medicine.
J Clin Invest. 2023 May 1;133(9):e169217. doi: 10.1172/JCI169217.
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.
院外心脏骤停的死亡率很高，长期生存率低。在确定能保护神经功能和提高心脏骤停后长期生存率的药物方面，存在着巨大的药理学知识差距。在本期 JCI 中，Li、Zhu 和同事报告了他们设计的一种 20 个氨基酸的细胞穿透肽（TAT-PHLPP9c），该肽拮抗磷酸酶 PHLPP1，防止 PHLPP1 介导的去磷酸化和 AKT 失活。TAT-PHLPP9c 在心脏骤停后维持 AKT 的激活，并导致 AKT 介导的对心脏、大脑和代谢的有益作用，从而增加心输出量和脑血流量，并挽救受影响组织中的 ATP 水平。TAT-PHLPP9c 改善了心脏骤停后小鼠和猪模型的神经功能结局和存活率。这些发现为药理学靶向 PHLPP1 可能是提高心脏骤停后长期生存率的一种有前途的方法提供了概念验证。
