Abstract 12098: S-nitrosoglutathione Reductase Deficiency Prevents Neurological Injury After Cardiac Arrest and Cardiopulmonary Resuscitation
Introduction: Nitric oxide (NO) exerts many of its effects via protein S-nitrosylation (SNO). Protein SNO levels are critically controlled by the activity of denitrosylase S-nitrosoglutathione reductase (GSNOR). The objective of this study was to examine the impact of enhanced protein SNO induced by GSNOR deficiency on the outcomes of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) in mice.
Methods and Results: Wild-type (WT) mice and mice deficient for GSNOR (GSNOR-/-) were subjected to CA for 8 min whereupon CPR was performed with chest compression and mechanical ventilation. There were no differences in characteristics before CA and during CPR except for lower mean blood pressure in GSNOR-/- mice at baseline. WT mice that were subjected to CA/CPR exhibited a poor 6-day survival rate (16.7%), depressed neurological function, and increased hydrogen peroxide production in the brain. In contrast, GSNOR-/- mice exhibited better neurological recovery, attenuated hydrogen peroxide production, and markedly improved 6-day survival rate (66.7%, P<0.05 vs WT). The protective effects of GSNOR deficiency were associated with markedly reduced mitochondria complex I activity in the brain at 5 min after CPR compared with sham-operated GSNOR-/- mice as evidenced by the ATP turnover rate in isolated cerebral mitochondria. Administration of a mitochondria-targeted S-nitrosothiol MitoSNO to WT mice 1min before CPR similarly depressed cerebral mitochondrial complex I activity and improved neurological outcomes, and survival rate. These results suggest that SNO-based inhibition of mitochondrial activity prevents ischemic neurological injury after CA and CPR.
Conclusions: GSNOR-deficiency improves outcomes after CA and CPR in mice at least in part by modulating mitochondrial complex I activity and reducing reactive oxygen species generation during early reperfusion phase. Pharmacological augmentation of protein SNO may limit long term neurological impairment and death after CA/CPR.
Author Disclosures: K. Hayashida: None. S. Hirai: None. K. Ikeda: None. S. Kai: None. E. Marutani: None. F. Ichinose: None.
- © 2015 by American Heart Association, Inc.