Skip Navigation

Publication Detail

Title: S-Nitrosoglutathione Reductase Is Essential for Protecting the Female Heart From Ischemia-Reperfusion Injury.

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

Published In Circ Res, (2018 11 09)

Abstract: 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.Because female hearts exhibit higher SNO levels, we hypothesized that GSNO-R is an essential component of sex-dependent cardioprotection in females.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.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.

PubMed ID: 30571462 Exiting the NIEHS site

MeSH Terms: Alcohol Dehydrogenase/antagonists & inhibitors; Alcohol Dehydrogenase/metabolism*; Animals; Benzamides/pharmacology; Benzamides/therapeutic use; Cardiotonic Agents/pharmacology; Cardiotonic Agents/therapeutic use; Enzyme Inhibitors/pharmacology; Enzyme Inhibitors/therapeutic use; Female; Heart/drug effects*; Male; Mice; Mice, Inbred C57BL; Myocardial Reperfusion Injury/drug therapy; Myocardial Reperfusion Injury/metabolism*; Myocardium/metabolism; Oxidative Stress; Pyrroles/pharmacology; Pyrroles/therapeutic use; Sex Factors

Back
to Top