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

• Published in: Circulation research Vol. 123; no. 11; pp. 1232 - 1243
• Main 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.
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 09.11.2018
• Subjects: 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; nitric oxide; reperfusion injury; formaldehyde; heart; reactive oxygen species
• ISSN: 0009-7330; 1524-4571; 1524-4571
• DOI: 10.1161/CIRCRESAHA.118.313956

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.