Abstract 17623: Estrogen-Mediated Small GTP-Binding Protein GDP Dissociation Stimulator Induction Contributes to Sex Differences in Resilience to Ferroptosis in Takotsubo Syndrome

Abstract

Introduction: Declining estrogen (E2) has been associated with disproportionate susceptibility to takotsubo syndrome (TTS) in postmenopausal women. Small GTP-binding protein GDP dissociation stimulator (SmgGDS), as a key modulator of cardiovascular disease, plays protective roles in reducing oxidative stress and exerts pleiotropic effects of statins. Whether SmgGDS levels are influenced by E2 status and the effect of SmgGDS on sex differences in TTS are poorly understood. Methods: Clinical data were reviewed from TTS inpatients. Echocardiography, immunofluorescence, and immunohistochemistry were performed together with expression analysis to uncover phenotypic and mechanism changes in sex differences in TTS-like wild-type ( WT ) and SmgGDS +/- mice. HL-1 cardiomyocytes were used to further examine molecular mechanisms. Results: In 14 TTS inpatients, TTS had a higher incidence in postmenopausal women as compared to premenopausal women and men. In murine TTS, female WT mice exhibited higher cardiac SmgGDS levels than male WT mice. Ovariectomy reduced SmgGDS expression in female WT mice, whereas E2 replacement reversed this effect. The physiological importance of this sex-specific E2-mediated SmgGDS response is underscored by the disparity in cardiac adaptation to isoproterenol (ISO) stimulation between both sexes of WT mice. E2-mediated SmgGDS induction conferred female cardioprotection against ferritinophagy-mediated ferroptosis. No such cardioprotection was observed in male WT mice and ovariectomized (OVX) female mice. A causal role for SmgGDS in this sex-specific cardioprotective adaptation was indicated, inasmuch as SmgGDS deficiency abolished E2-modulated cardioprotection against ferritinophagy and aggravated TTS progression in both sexes. Consistently, knockdown of SmgGDS in HL-1 cardiomyocytes exacerbated ferritinophagy and abrogated the protective role of E2 against ferritinophagy. Mechanistically, our findings revealed that SmgGDS deficiency abolished E2-conferred protection against ferritinophagy through activating AMPK/mTOR pathway. Conclusions: These results demonstrate SmgGDS is a central mediator of E2-conferred female cardioprotection against ferritinophagy-mediated ferroptosis in TTS.