Abstract Body: Introduction: Pre-menopausal women exhibit reduced susceptibility to myocardial infarction (MI) injury through estrogen-mediated cardioprotection. Paradoxically, female mice deficient in S-nitrosoglutathione reductase (GSNOR^KO), which exhibit elevated protein S-nitrosylation, show impaired cardiac function and increased mortality post-MI versus WT mice. Whether estrogen retains its cardioprotective effects in a high S-nitrosylation (nitroso-redox imbalance) environment remains unknown.
Hypothesis: GSNOR deficiency enhances pathological remodeling post-MI in female mice which is attenuated by estrogen depletion (ovariectomized mice, OVX).
Methods: Intact and OVX WT and GSNOR^KO female mice (3 months old; N= ± 5/group) underwent MI via left anterior descending (LAD) artery occlusion. Echocardiography assessed ejection fraction (EF), end-diastolic (EDV) and end-systolic (ESV) volumes at baseline, 1- and 8-weeks post-MI. Inclusion criteria: infarct size >30% and EF <40% at week 1. To investigate the transcriptional mechanisms underlying GSNOR deficiency in ischemic injury, bulk RNA-seq was performed comparing parental and GSNOR^KO female hiPSC-derived cardiomyocytes (hiPSC-CMs, N=3) under hypoxia.
Results: EF declined across all groups at 8 weeks post-MI (P<0.0001). GSNOR^KO intact mice exhibited greater EDV versus WT intact (136.2±46.3 vs. 100.9±9.2 µL; P<0.05), with no difference between GSNOR^KO OVX and WT OVX. GSNOR^KO intact mice showed significantly greater EDV (136.2±46.3 vs. 90±32.8 µL; P<0.01) and ESV (113±49 vs. 67.7±34.7 µL; P<0.01) versus GSNOR^KO OVX mice at 8 weeks. RNA-seq revealed upregulation of TGF-β signaling and ECM remodeling genes (collagens, periostin, TGF-β receptors) in GSNOR^KO hiPSC-CMs under hypoxia (FDR<0.05).
Conclusions: Estrogen deficiency attenuates pathological LV remodeling in GSNOR^KO females following MI, suggesting estrogen may promote adverse remodeling in a nitroso-redox imbalance environment. GSNOR^KO hiPSC-CMs under hypoxia demonstrate upregulation of TGF-β–associated ECM remodeling pathways, linking dysregulated S-nitrosylation to post-MI cardiac remodeling.