Faculty Collaboration Database

GSNOR deletion differentially alters age-related cardiac function in a sex-dependent manner. Am J Physiol Heart Circ Physiol 2026 Jan 01;330(1):H253-H264

Date

12/18/2025

Pubmed ID

41407313

Pubmed Central ID

PMC12954546

DOI

10.1152/ajpheart.00681.2025

Scopus ID

2-s2.0-105026900143 (requires institutional sign-in at Scopus site)   1 Citation

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 two-dimensional echocardiography measurements in M-mode on male and female, wild-type (WT) and GSNOR^-/- 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 GSNOR^-/-. 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 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 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.NEW & NOTEWORTHY 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.

Author List

Ebenebe OV, Kabir R, Booher A, Garbus H, Cohen CD, Jani V, Lin BL, Adamo L, Kohr MJ

Author

Brian L. Lin PhD Assistant Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Age Factors
Aging
Alcohol Dehydrogenase
Aldehyde Oxidoreductases
Animals
Calcium Signaling
Female
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myocardial Contraction
Myocytes, Cardiac
Sarcomeres
Sex Factors
Ventricular Function, Left