Improvement in Outcomes After Cardiac Arrest and Resuscitation by Inhibition of S-Nitrosoglutathione Reductase

Kei Hayashida, Aranya Bagchi, Yusuke Miyazaki, Shuichi Hirai, Divya Seth, Michael G. Silverman, Emanuele Rezoagli, Eizo Marutani, Naohiro Mori, Aurora Magliocca, Xiaowen Liu, Lorenzo Berra, Allyson G. Hindle, Michael W. Donnino, Rajeev Malhotra, Matthews O. Bradley, Jonathan S. Stamler, Fumito Ichinose

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Abstract

BACKGROUND: The biological effects of nitric oxide are mediated via protein S-nitrosylation. Levels of S-nitrosylated protein are controlled in part by the denitrosylase, S-nitrosoglutathione reductase (GSNOR). The objective of this study was to examine whether GSNOR inhibition improves outcomes after cardiac arrest and cardiopulmonary resuscitation (CA/CPR). METHODS: Adult wild-type C57BL/6 and GSNOR-deleted (GSNOR-/-) mice were subjected to potassium chloride-induced CA and subsequently resuscitated. Fifteen minutes after a return of spontaneous circulation, wild-type mice were randomized to receive the GSNOR inhibitor, SPL-334.1, or normal saline as placebo. Mortality, neurological outcome, GSNOR activity, and levels of S-nitrosylated proteins were evaluated. Plasma GSNOR activity was measured in plasma samples obtained from post-CA patients, preoperative cardiac surgery patients, and healthy volunteers. RESULTS: GSNOR activity was increased in plasma and multiple organs of mice, including brain in particular. Levels of protein S-nitrosylation were decreased in the brain 6 hours after CA/CPR. Administration of SPL-334.1 attenuated the increase in GSNOR activity in brain, heart, liver, spleen, and plasma, and restored S-nitrosylated protein levels in the brain. Inhibition of GSNOR attenuated ischemic brain injury and improved survival in wild-type mice after CA/CPR (81.8% in SPL-334.1 versus 36.4% in placebo; log rank P=0.031). Similarly, GSNOR deletion prevented the reduction in the number of S-nitrosylated proteins in the brain, mitigated brain injury, and improved neurological recovery and survival after CA/CPR. Both GSNOR inhibition and deletion attenuated CA/CPR-induced disruption of blood brain barrier. Post-CA patients had higher plasma GSNOR activity than did preoperative cardiac surgery patients or healthy volunteers ( P<0.0001). Plasma GSNOR activity was positively correlated with initial lactate levels in postarrest patients (Spearman correlation coefficient=0.48; P=0.045). CONCLUSIONS: CA and CPR activated GSNOR and reduced the number of S-nitrosylated proteins in the brain. Pharmacological inhibition or genetic deletion of GSNOR prevented ischemic brain injury and improved survival rates by restoring S-nitrosylated protein levels in the brain after CA/CPR in mice. Our observations suggest that GSNOR is a novel biomarker of postarrest brain injury as well as a molecular target to improve outcomes after CA.

Original languageEnglish
Pages (from-to)815-827
Number of pages13
JournalCirculation
Volume139
Issue number6
DOIs
Publication statusPublished - 2019 Feb 5
Externally publishedYes

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Keywords

  • cardiopulmonary resuscitation
  • heart arrest
  • nitric oxide
  • S-Nitrosoglutathione

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Hayashida, K., Bagchi, A., Miyazaki, Y., Hirai, S., Seth, D., Silverman, M. G., Rezoagli, E., Marutani, E., Mori, N., Magliocca, A., Liu, X., Berra, L., Hindle, A. G., Donnino, M. W., Malhotra, R., Bradley, M. O., Stamler, J. S., & Ichinose, F. (2019). Improvement in Outcomes After Cardiac Arrest and Resuscitation by Inhibition of S-Nitrosoglutathione Reductase. Circulation, 139(6), 815-827. https://doi.org/10.1161/CIRCULATIONAHA.117.032488