GSNOR deletion differentially alters age-related cardiac function in a sex-dependent manner

<i>S</i>-nitrosoglutathione reductase (GSNOR), a regulator of protein <i>S</i>-nitrosylation (SNO), has been proposed as a longevity protein. GSNOR signaling has been implicated in both the alleviation and exacerbation of aging. In the context of ischemia-reperfusion injury, we previously showed a sex-dependent response to GSNOR inhibition; cardiac damage was alleviated in males and exacerbated in females. Considering sex differences in the incidence of cardiovascular disease with age, we investigated the effect of GSNOR deletion (^-/-) on age-related changes in cardiac function. We performed longitudinal two-dimensional echocardiography measurements in M-mode on male and female, wild-type (WT) and <i>GSNOR</i>^-/- mice at young (3-4 mo), middle (13-15 mo), and old age (18-20 mo). Left ventricular wall thickness and ejection fraction decreased with age in WT mice but were maintained in <i>GSNOR</i>^-/-. Western blot and GSNOR activity assays showed GSNOR activity and expression decreased with age in WT females. Isolated cardiomyocyte force-coupling analysis showed that increasing age was inversely correlated with sarcomere shortening and Ca²⁺ release kinetics in WT males but not <i>GSNOR</i>^-/-. WT females showed slower Ca²⁺ re-uptake after contraction and time to peak sarcomere shortening, but all other parameters were maintained. <i>GSNOR</i>^-/- females exhibited slower Ca²⁺ re-uptake and decreased sarcomere shortening. Proteomic analysis of SNO from females showed increased modification of pyruvate dehydrogenase, E1β, and dihydrolipoamide dehydrogenase in young WT females relative to middle-aged mice. Together, our data suggest that GSNOR deletion is beneficial in males by maintaining cardiac function; although the absence of GSNOR in females removes an age-essential SNO imbalance, which may exacerbate age-related pathology.<b>NEW & NOTEWORTHY</b> GSNOR deficiency appears beneficial to cardiac aging in both sexes, but at the cellular level, we discovered a sex disparity and the potential for underlying cellular dysfunction in female hearts. Taken together, GSNOR deficiency may present a mechanism through which the female heart specifically is at a higher risk of age-related cardiovascular disease and may represent a potential clinical target.