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

Abstract

Rationale: Protein S-nitros(yl)ation (SNO) has been implicated as an essential mediator of nitric oxide-dependent cardioprotection. Compared to males, female hearts exhibit higher baseline levels of protein SNO and associated with this, reduced susceptibility to myocardial ischemia-reperfusion (I/R) 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: Since 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 wildtype mouse hearts were subjected to ex vivo I/R injury with or without GSNO-R inhibition (N6022). Control female hearts exhibited enhanced functional recovery and decreased infarct size vs. 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 I/R 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 while GSNO-R inhibition significantly increased SNO at the cardioprotective Cys39 residue of NADH dehydrogenase subunit 3 in males, SNO-ND3 levels were surprisingly reduced in N6022-treated female hearts. Since GSNO-R also acts as a formaldehyde dehydrogenase, we examined post-ischemic formaldehyde levels and found that they were nearly 2-fold higher in N6022-treated female hearts compared to non-treated 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.

Core functional nodes and sex-specific pathways in human ischaemic and dilated cardiomyopathy

“…We are the first to report the interaction of TMAO with gender in human heart failure myocardium, which has important implications when considering that this microbiome-derived metabolite has been reported widely as a mediator of atherosclerosis, platelet activation, and myocardial infarction [27][28][29]65 ; our data suggests it may be a contributor to the divergence in heart failure outcomes in men and women. An interaction of nitric oxide deficiency with gender in recovery post ischaemia has been reported before in mice 66 , and S-nitrosoglutathione reductase was reported to be a critical sex-dependent mediator of myocardial protein Snitrosylation in mice 67 and murine ex vivo hearts 68 (more active in females); S-nitrosylation is reported as an essential mediator of nitric oxide-dependent cardioprotection 67 . Other work in mice revealed that nitroglycerin-induced calcitonin generelated peptide release is eNOS-dependent, with a greater response in females 69 , and estrogen has been shown to upregulate NOS in neonatal rat cardiomyocytes 70 .…”

Ischemia/Reperfusion Injury Revisited: An Overview of the Latest Pharmacological Strategies

“…They are divided into subpopulations that vary structurally and functionally to such an extent that it is possible to observe distinctions even within the very same tissue, as explained by Hollander et al regarding the categorization of cardiac mitochondria into subsarcolemmal (SSM) and interfibrillar types (IFM) [33]. Furthermore, the notion that mitochondrial metabolism is related both to age and sex has been demonstrated empirically several times based on different levels of sensitivity to Ca 2+ [34], mitochondrial permeability transition pore (mPTP) responsiveness [35] and myocardial protection in IRI [36]. These findings should definitely be considered during the development/evaluation of therapeutic approaches to I/R-linked diseases and surgical procedures.…”

Pharmacological Inhibition of S-Nitrosoglutathione Reductase Reduces Cardiac Damage Induced by Ischemia–Reperfusion

“…Importantly, in a similar study to this one, Casin et al, using another GSNOR inhibitor, N6022, showed similar effects regarding cardioprotection in male mice but not in females [ 47 ]. In fact, in female mice, GSNOR inhibition worsened the damage produced by I–R.…”