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bioRxiv · 10.1101/2025.07.28.667309

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

Ebenebe, O. V.·Kabir, R.·Booher, A.·Garbus-Grant, H.·Cohen, C. D.·Jani, V.·Lin, B. L.·Adamo, L.·Kohr, M. J.
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Abstract

S-nitrosoglutathione reductase (GSNOR), a regulator of protein S-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 2D-echocardiography measurements in M-Mode on male and female, wildtype (WT) and GSNOR-/- mice at young (3-4 months), middle (13-15 months) and old age (18-20 months). Left ventricular wall thickness and ejection fraction decreased with age in WT mice but was maintained in GSNOR-/-. Western blot and GSNOR-activity assay showed GSNOR activity and expression decreased with age in WT females alone. Isolated cardiomyocyte force-coupling analysis showed increasing age was inversely correlated with sarcomere shortening and Ca2+ release kinetics in WT males, but not GSNOR-/-. WT females showed slower Ca2+ re-uptake after contraction and time to peak sarcomere shortening, but all other parameters were maintained. GSNOR-/- females exhibited slower Ca2+ re-uptake and decreased sarcomere shortening. Proteomic analysis of SNO from females showed upregulation of Pyruvate Dehydrogenase, E1 Beta and Dihydrolipoamide dehydrogenase in young WT females relative to middle-age mice. Together our data suggest that GSNOR deletion is cardioprotective by maintaining cardiac function in males; while in females the absence of GSNOR removes an age-essential SNO-imbalance, which may exacerbate pathologies.

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Ebenebe, O. V., Kabir, R., Booher, A., Garbus-Grant, H., Cohen, C. D., Jani, V., Lin, B. L., Adamo, L., Kohr, M. J.. 2025-07-31. GSNOR deletion differentially alters age-related cardiac function in a sex-dependent manner.. https://doi.org/10.1101/2025.07.28.667309

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