A cell-penetrating PHLPP peptide improves cardiac arrest survival in murine and swine models.
Jing LiXiangdong ZhuMatt T OberdierChunpei LeeShaoxia LinSarah J FinkCody N JusticeKevin QinAndrew W BegemanFrederick C DamenHajwa KimJiwang ChenKejia CaiHenry R HalperinTerry L Vanden HoekPublished in: The Journal of clinical investigation (2023)
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.
Keyphrases
- cardiac arrest
- cardiopulmonary resuscitation
- blood pressure
- cerebral blood flow
- free survival
- signaling pathway
- amino acid
- physical activity
- heart failure
- cell proliferation
- protein kinase
- left ventricular
- cardiovascular disease
- study protocol
- cell therapy
- mental health
- type diabetes
- open label
- coronary artery disease
- cardiovascular events
- functional connectivity
- risk factors
- mesenchymal stem cells
- stem cells
- randomized controlled trial
- cell cycle
- white matter
- blood glucose
- insulin resistance
- phase ii
- case control