A cell-penetrating PHLPP peptide improves cardiac arrest survival in murine and swine models
Jing Li, Xiangdong Zhu, Matt T. Oberdier, Chunpei Lee, Shaoxia Lin, Sarah J. Fink, Cody N. Justice, Kevin Qin, Andrew W. Begeman, Frederick C. Damen, Hajwa Kim, Jiwang Chen, Kejia Cai, Henry R. Halperin, Terry L. Vanden Hoek
Jing Li, Xiangdong Zhu, Matt T. Oberdier, Chunpei Lee, Shaoxia Lin, Sarah J. Fink, Cody N. Justice, Kevin Qin, Andrew W. Begeman, Frederick C. Damen, Hajwa Kim, Jiwang Chen, Kejia Cai, Henry R. Halperin, Terry L. Vanden Hoek
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Research Article

A cell-penetrating PHLPP peptide improves cardiac arrest survival in murine and swine models

Abstract

Out-of-hospital cardiac arrest is a leading cause of death in the US, with a mortality rate over 90%. Preclinical studies demonstrate that cooling during cardiopulmonary resuscitation (CPR) is highly beneficial, but can be challenging to implement clinically. No medications exist for improving long-term cardiac arrest survival. We have developed a 20–amino acid peptide, TAT-PHLPP9c, that mimics cooling protection by enhancing AKT activation via PH domain leucine-rich repeat phosphatase 1 (PHLPP1) inhibition. Complementary studies were conducted in mouse and swine. C57BL/6 mice were randomized into blinded saline control and peptide-treatment groups. Following a 12-minute asystolic arrest, TAT-PHLPP9c was administered intravenously during CPR and significantly improved the return of spontaneous circulation, mean arterial blood pressure and cerebral blood flow, cardiac and neurological function, and survival (4 hour and 5 day). It inhibited PHLPP-NHERF1 binding, enhanced AKT but not PKC phosphorylation, decreased pyruvate dehydrogenase phosphorylation and sorbitol production, and increased ATP generation in heart and brain. TAT-PHLPP9c treatment also reduced plasma taurine and glutamate concentrations after resuscitation. The protective benefit of TAT-PHLPP9c was validated in a swine cardiac arrest model of ventricular fibrillation. In conclusion, TAT-PHLPP9c may improve neurologically intact cardiac arrest survival without the need for physical cooling.

Authors

Jing Li, Xiangdong Zhu, Matt T. Oberdier, Chunpei Lee, Shaoxia Lin, Sarah J. Fink, Cody N. Justice, Kevin Qin, Andrew W. Begeman, Frederick C. Damen, Hajwa Kim, Jiwang Chen, Kejia Cai, Henry R. Halperin, Terry L. Vanden Hoek

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Figure 3

TAT-PHLPP9c improved 4-hour survival, brain perfusion, and cardiac function when administered during CPR after mouse CA.

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TAT-PHLPP9c improved 4-hour survival, brain perfusion, and cardiac funct...
(A) Kaplan-Meier 4-hour survival plot demonstrated that, compared with saline, TAT-PHLPP9c administered at various doses (4. 7.5 and 16 mg/kg) improved 4-hour survival following 12 minutes of arrest, with 7.5 mg/kg being a lower dose with highest benefit. No significant difference between the doses of 7.5 and 16 mg/kg. n = 11 in each group. A log-rank (Mantel-Cox) test using Kaplan-Meier curves was performed. *P < 0.01 between saline and TAT-PHLPP9c. (B) Longitudinal MRI revealed that TAT-PHLPP9c treatment significantly increased CBF following 8 minutes of arrest. Anatomical T2-weighted MRI images of the brain and the color-coded CBF contrast maps at varied time points after ROSC (40, 60, 80, 100, and 120 minutes) overlaid onto the anatomical T2-weighted images from a representative control mouse (top) and a treated mouse (bottom). (C) Statistical analysis of rCBF MRI contrast over time from saline (black) and TAT-PHLPP9c (green). Paired, 2-tailed t test was used. #P < 0.05. Data are represented as mean ± SD for 5 mice. (D) Representative echocardiography SAX images revealed that TAT-PHLPP9c improved heart ventricular contraction after ROSC. SAX images of cross-sectional view of left and right ventricles captured at R80 after ROSC from a representative control mouse (top) and a treated mouse (bottom). (E) Compared with saline, TAT-PHLPP9c improved cardiac function, including CO, EF, FS, and SV. The improvement was significant at R80. Paired, 2-tailed t test was used. #P < 0.05; *P < 0.01. Data are represented as mean ± SD for 4 mice.