title: A novel pharmacological strategy by PTEN inhibition for improving metabolic resuscitation and survival after mouse cardiac arrest.
abstract: Sudden cardiac arrest (SCA) is a leading cause of death in the United States. Despite return of spontaneous circulation, patients die due to post-SCA syndrome that includes myocardial dysfunction, brain injury, impaired metabolism, and inflammation. No medications improve SCA survival. Our prior work suggests that optimal Akt activation is critical for cooling protection and SCA recovery. Here, we investigate a small inhibitor of PTEN, an Akt-related phosphatase present in heart and brain, as a potential therapy in improving cardiac and neurological recovery after SCA. Anesthetized adult female wild-type C57BL/6 mice were randomized to pretreatment of VO-OHpic (VO) 30 min before SCA or vehicle control. Mice underwent 8 min of KCl-induced asystolic arrest followed by CPR. Resuscitated animals were hemodynamically monitored for 2 h and observed for 72 h. Outcomes included heart pressure-volume loops, energetics (phosphocreatine and ATP from (31)P NMR), protein phosphorylation of Akt, GSK3β, pyruvate dehydrogenase (PDH) and phospholamban, circulating inflammatory cytokines, plasma lactate, and glucose as measures of systemic metabolic recovery. VO reduced deterioration of left ventricular maximum pressure, maximum rate of change in the left ventricular pressure, and Petco2 and improved 72 h neurological intact survival (50% vs. 10%; P < 0.05). It reduced plasma lactate, glucose, IL-1β, and Pre-B cell colony enhancing factor, while increasing IL-10. VO increased phosphorylation of Akt and GSK3β in both heart and brain, and cardiac phospholamban phosphorylation while reducing p-PDH. Moreover, VO improved cardiac bioenergetic recovery. We concluded that pharmacologic PTEN inhibition enhances Akt activation, improving metabolic, cardiovascular, and neurologic recovery with increased survival after SCA. PTEN inhibitors may be a novel pharmacologic strategy for treating SCA.
authors: Program in Advanced Resuscitation Medicine, Center for Cardiovascular Research, and Department of Emergency Medicine, University of Illinois Hospital & Health Sciences System, Chicago, Illinois;
authors: Jing
authors: J
authors: Li
authors: Program in Advanced Resuscitation Medicine, Center for Cardiovascular Research, and Department of Emergency Medicine, University of Illinois Hospital & Health Sciences System, Chicago, Illinois;
authors: Huashan
authors: H
authors: Wang
authors: Program in Advanced Resuscitation Medicine, Center for Cardiovascular Research, and Department of Emergency Medicine, University of Illinois Hospital & Health Sciences System, Chicago, Illinois; Department of Emergency Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science & Technology, China;
authors: Qiang
authors: Q
authors: Zhong
authors: Program in Advanced Resuscitation Medicine, Center for Cardiovascular Research, and Department of Emergency Medicine, University of Illinois Hospital & Health Sciences System, Chicago, Illinois;
authors: Xiangdong
authors: X
authors: Zhu
authors: Program in Advanced Resuscitation Medicine, Center for Cardiovascular Research, and Department of Emergency Medicine, University of Illinois Hospital & Health Sciences System, Chicago, Illinois; Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taiwan;
authors: Sy-Jou
authors: SJ
authors: Chen
authors: Program in Advanced Resuscitation Medicine, Center for Cardiovascular Research, and Department of Emergency Medicine, University of Illinois Hospital & Health Sciences System, Chicago, Illinois; Emergency Department, Chinese PLA General Hospital, Beijing, China;
authors: Yuanyu
authors: Y
authors: Qian
authors: Program in Advanced Resuscitation Medicine, Center for Cardiovascular Research, and Department of Emergency Medicine, University of Illinois Hospital & Health Sciences System, Chicago, Illinois;
authors: Jim
authors: J
authors: Costakis
authors: Program in Advanced Resuscitation Medicine, Center for Cardiovascular Research, and Department of Emergency Medicine, University of Illinois Hospital & Health Sciences System, Chicago, Illinois;
authors: Gabrielle
authors: G
authors: Bunney
authors: Section of Emergency Medicine, Department of Medicine, University of Chicago, Chicago, Illinois;
authors: David G
authors: DG
authors: Beiser
authors: Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois; and.
authors: Alan R
authors: AR
authors: Leff
authors: Program in Integrative Cardiac Metabolism, Center for Cardiovascular Research, and Department of Physiology and Biophysics, University of Illinois Hospital & Health Sciences System, Chicago, Illinois.
authors: E Douglas
authors: ED
authors: Lewandowski
authors: Program in Integrative Cardiac Metabolism, Center for Cardiovascular Research, and Department of Physiology and Biophysics, University of Illinois Hospital & Health Sciences System, Chicago, Illinois.
authors: J Michael
authors: JM
authors: ÓDonnell
authors: Program in Advanced Resuscitation Medicine, Center for Cardiovascular Research, and Department of Emergency Medicine, University of Illinois Hospital & Health Sciences System, Chicago, Illinois; tvh@uic.edu.
authors: Terry L
authors: TL
authors: Vanden Hoek
mesh_terms: D000818:Animals; D016207:Cytokines / Q000097:blood; D004734:Energy Metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006323:Heart Arrest / Q000188:drug therapy* / Q000378:metabolism; D006439:Hemodynamics; D051379:Mice; D008810:Mice, Inbred C57BL; D009942:Organometallic Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors*; D012151:Resuscitation / Q000379:methods
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; C000600334:VO-OHpic; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: Akt; PTEN; inflammation; metabolism; sudden cardiac arrest