Journal
FASEB JOURNAL
Volume 37, Issue 6, Pages -Publisher
WILEY
DOI: 10.1096/fj.202300083R
Keywords
endothelial dysfunction; estrogen; ferroptosis; NRF2; postmenopausal atherosclerosis
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Oxidative stress and lipid metabolism disorder caused by estrogen deficiency contribute to postmenopausal atherosclerosis. This study used ovariectomized female ApoE(-/-) mice fed with a high-fat diet to simulate postmenopausal atherosclerosis. The progression of atherosclerosis was accelerated in these mice, accompanied by increased indicators of ferroptosis. Estradiol and a ferroptosis inhibitor showed protective effects against atherosclerosis and inhibited lipid peroxidation and iron deposition in endothelial cells. Additionally, estradiol exhibited anti-ferroptosis effects by improving mitochondrial dysfunction and upregulating GPX4 expression. NRF2 inhibition attenuated the protective effects of estradiol against ferroptosis. This research highlights the role of endothelial cell ferroptosis in postmenopausal atherosclerosis and the protective effects of NRF2/GPX4 pathway activation by estradiol.
Oxidative stress and lipid metabolism disorder caused by estrogen deficiency are regarded as the main causes of postmenopausal atherosclerosis, but the underlying mechanisms remain still unclear. In this study, ovariectomized (OVX) female ApoE(-/-) mice fed with high-fat diet were used to imitate postmenopausal atherosclerosis. The atherosclerosis progression was significantly accelerated in OVX mice, accompanied by the upregulation of ferroptosis indicators, including increased lipid peroxidation and iron deposition in the plaque and the plasma. While both estradiol (E2) and ferroptosis inhibitor ferrostatin-1 alleviated atherosclerosis in OVX mice, with the inhibition of lipid peroxidation and iron deposition, as well as the upregulation of xCT and GPX4, especially in endothelial cells. We further investigated the effects of E2 on ferroptosis in endothelial cells induced by oxidized-low-density lipoprotein or ferroptosis inducer Erastin. It was found that E2 exhibited anti-ferroptosis effect through antioxidative functions, including improving mitochondrial dysfunction and upregulating GPX4 expression. Mechanistically, NRF2 inhibition attenuated the effect of E2 against ferroptosis as well as the upregulation of GPX4. Our findings revealed that endothelial cell ferroptosis played a pivotal role in postmenopausal atherosclerosis progression, and the NRF2/GPX4 pathway activation contributed to the protection of E2 against endothelial cell ferroptosis.
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