Mild hypoxia as therapy for post-ischemic mitochondrial injury

Introduction: Mitochondrial injury occurs following cellular ischemia in the setting of myocardial infarction, stroke, and cardiac arrest (CA). Effective strategies for reducing injury are limited. Hypoxia has shown benefit in reversing mitochondrial mediated neurodegenerative disease but is little studied in the setting of post-ischemic injury and is regarded as potentially harmful. In this study, we investigated the effects of mild hypoxia on global post-ischemic injury following CA. We hypothesized that brief mild hypoxia following CA would improve mitochondrial function resulting in improved cellular metabolism and physiological recovery. Methods and Results: Anesthetized C57BL6 mice underwent brief asystolic CA (12 min) followed bycardiopulmonary resuscitation(CPR). One hour following successful CPR, mice were randomized to receive a brief episode (6 hours) of normoxia (21% O2) or hypoxia (10% O2) in an environmental chamber. Post intervention, the mice were returned to room air (21% O2). Mild hypoxia improved cardiac mitochondrial complex 1 respiration in the heart by 28% and ATP-related oxygen consumption by 49% (n=3, P<0.05 vs normoxia, respectively) compared to normoxia treated mice. Hypoxia was further associated with improved glucose oxidation in heart as evidenced by decreases in pyruvate dehydrogenase kinase 4 (PDK4) gene and protein expression (n=4, P<0.05 vs normoxia, respectively) as well as decreases in pyruvate dehydrogenase phosphorylation (n=4, P<0.05, respectively) in heart. Hypoxia decreased lactate dehydrogenase (LDH) expression and lactate concentration in heart compared to normoxia treated controls (n=4, P<0.05 vs normoxia, respectively). ROS production in heart by 20% (n=6, P<0.05) was also decreased by mild hypoxia when compared to normoxia post CA. These changes were associated with improved recovery of myocardial function, neurological recovery, and 10-day survival following CA (n=13, P<0.05 vs normoxia, respectively). Conclusion: Brief mild hypoxia treatment following global ischemic injury paradoxically improved recovery of myocardial mitochondrial respiration and metabolism and was associated with improved physiological recovery and survival. Post-ischemia hypoxia is a potential therapeutic strategy for mitochondrial ischemic injury and requires further study. No financial disclosures. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.