S-nitrosoglutathione reductase is essential for protecting the female heart from ischemia-reperfusion injury

Kevin M. Casin, Jonathan Fallica, Nathan Mackowski, Ryne J. Veenema, Ashley Chan, Amanda St. Paul, Guangshuo Zhu, Djahida Bedja, Shyam Biswal, Mark J. Kohr

Research output: Contribution to journalArticlepeer-review

Abstract

Rationale: Protein S-nitros(yl)ation (SNO) has been implicated as an essential mediator of nitric oxide-dependent cardioprotection. Compared with males, female hearts exhibit higher baseline levels of protein SNO and associated with this, reduced susceptibility to myocardial ischemia-reperfusion injury. Female hearts also exhibit enhanced S-nitrosoglutathione reductase (GSNO-R) activity, which would typically favor decreased SNO levels as GSNO-R mediates SNO catabolism. Objective: Because female hearts exhibit higher SNO levels, we hypothesized that GSNO-R is an essential component of sex-dependent cardioprotection in females. Methods and Results: Male and female wild-type mouse hearts were subjected to ex vivo ischemia-reperfusion injury with or without GSNO-R inhibition (N6022). Control female hearts exhibited enhanced functional recovery and decreased infarct size versus control males. Interestingly, GSNO-R inhibition reversed this sex disparity, significantly reducing injury in male hearts, and exacerbating injury in females. Similar results were obtained with male and female GSNO-R−/− hearts using ex vivo and in vivo models of ischemia-reperfusion injury. Assessment of SNO levels using SNO-resin assisted capture revealed an increase in total SNO levels with GSNO-R inhibition in males, whereas total SNO levels remained unchanged in females. However, we found that although GSNO-R inhibition significantly increased SNO at the cardioprotective Cys39 residue of nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 3 in males, SNO-NADH dehydrogenase subunit 3 levels were surprisingly reduced in N6022-treated female hearts. Because GSNO-R also acts as a formaldehyde dehydrogenase, we examined postischemic formaldehyde levels and found that they were nearly 2-fold higher in N6022-treated female hearts compared with nontreated hearts. Importantly, the mitochondrial aldehyde dehydrogenase 2 activator, Alda-1, rescued the phenotype in GSNO-R−/− female hearts, significantly reducing infarct size. Conclusions:These striking findings point to GSNO-R as a critical sex-dependent mediator of myocardial protein SNO and formaldehyde levels and further suggest that different therapeutic strategies may be required to combat ischemic heart disease in males and females.

Original languageEnglish (US)
Pages (from-to)1232-1243
Number of pages12
JournalCirculation research
Volume123
Issue number11
DOIs
StatePublished - 2018

Keywords

  • Formaldehyde
  • Heart
  • Nitric oxide
  • Reactive oxygen species
  • Reperfusion injury

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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