Abstract P3116: Age-Related Cardiac Changes In S-Nitrosoglutathione Reductase Knockout Mice

Abstract

Age associated cardiac aging differs between males and females, yet these age-related sex-dimorphic pathways remain poorly explored. We have previously shown that inhibition of S-nitrosoglutathione reductase (GSNOR) was cardioprotective during ischemic injury in male but not female mice. We therefore, hypothesized that GSNOR activity might play a role in sex-related differences in cardiac aging, and GSNOR deletion (KO) might exacerbate age-related cardiac dysfunction in females but not males. WT and KO mice underwent longitudinal 2D-echocardiography at 4, 7, 10 and 14 months of age, and echocardiographic data were analyzed with mixed-effects analysis. We saw a significant decrease in GSNOR activity in old (18 months) WT mice relative to young (4 months) in both sexes but more pronounced in males (p<0.0001) vs. females (p=0.02). Left ventricular (LV) internal diameter at end-diastole significantly increased with age in WT males (2.65 ± 0.02 to 3.60 ± 0.13) and females (2.61 ± 0.02 to 3.32 ± 0.04) with a significant effect of sex across age (p<0.0001). LV Mass (indexed to group body weight at 18 months) increased with age in both males (82 ± 2 to 127 ± 3) and females (85 ± 3 to 113 ± 3) with a significant age and sex interaction (p<0.0001). Similar trends were observed for other echocardiographic parameters. Contrary to our hypothesis, the age- and sex-related differences observed in WT were absent in KO mice. LV internal diameter at end-diastole and LV Mass did not significantly change in male or female KO mice from 4 to 14 months of age neither did the majority of echocardiographic parameters tested. No differences were observed between male and female KO mice. Taken together, our data show that GSNOR deletion attenuates aging-induced cardiac dysfunction and abrogates age-related sex differences in the mouse heart.