Literature summary for 1.1.1.284 extracted from

Casin, K.M.; Fallica, J.; Mackowski, N.; Veenema, R.J.; Chan, A.; St Paul, A.; Zhu, G.; Bedja, D.; Biswal, S.; Kohr, M.J.
S-Nitrosoglutathione reductase is essential for protecting the female heart from ischemia-reperfusion injury (2018), Circ. Res., 123, 1232-1243 .

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Protein Variants

Protein Variants	Comment	Organism
additional information	genetic deletion of GSNO-R. After 20 minutes of global ischemia and 60 minutes of reperfusion, contractile function is significantly impaired in male and female hearts, but post-ischemic functional recovery is significantly higher in female hearts and infarct size is reduced. Male GSNO-R-/- hearts show a significant reduction in infarct size compared to wild-type, while female GSNO-R-/- hearts show a significant increase in infarct size compared to wild-type	Mus musculus

Inhibitors

Inhibitors	Comment	Organism	Structure
3-(5-(4-(1H-imidazol-1-yl) phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl) propionic acid	N6022, a specific and potent GSNO-R inhibitor. N6022 inhibits the GSNO-R-mediated metabolism of GSNO and formaldehyde in the heart	Mus musculus

Organism

Organism	UniProt	Comment	Textmining
Mus musculus	P28474	-	-
Mus musculus C57BL/6J	P28474	-	-

Source Tissue

Source Tissue	Comment	Organism	Textmining
heart	-	Mus musculus	-

Synonyms

Synonyms	Comment	Organism
ADH5	-	Mus musculus
alcohol dehydrogenase class-3	UniProt	Mus musculus
GSNO-R	-	Mus musculus
S-nitrosoglutathione reductase	-	Mus musculus

General Information

General Information	Comment	Organism
malfunction	control female hearts exhibit enhanced functional recovery and decreased infarct size vs. control males. GSNO-R inhibition reverses this sex disparity, significantly reducing injury in male hearts, and exacerbating injury in females. Similar results are 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 reveals an increase in total SNO levels with GSNO-R inhibition in males, whereas total SNO levels remain unchanged in females. While GSNO-R inhibition significantly increases SNO at the cardioprotective Cys39 residue of NADH dehydrogenase subunit 3 in males, SNO-ND3 levels are surprisingly reduced in N6022-treated female hearts. Since GSNO-R also acts as a formaldehyde dehydrogenase, post-ischemic formaldehyde levels are examined, they are nearly 2fold higher in N6022-treated female hearts compared to non-treated hearts. The mitochondrial aldehyde dehydrogenase 2 activator, Alda-1, rescues the phenotype in GSNO-R-/- female hearts, significantly reducing infarct size. Male GSNO-R-/- mice weigh significantly less than male wild-type mice. Male GSNO-R-/- hearts show a significant reduction in infarct size compared to wild-type. GSNO-R inhibition increases post-ischemic free formaldehyde levels in female hearts, and mitochondrial aldehyde dehydrogenase 2 activation reduces I/R injury in female GSNO-R-/- hearts. But formaldehyde does not compete with SNO for the modification of common cysteine residues	Mus musculus
physiological function	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. Since female hearts exhibit higher SNO levels, GSNO-R seems to be an essential component of sex-dependent cardioprotection in females. GSNO-R is a critical sex-dependent mediator of myocardial protein SNO and formaldehyde levels. GSNO-R activity is significantly enhanced in female hearts at baseline vs. males	Mus musculus

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Release 2023.1 (January 2023)