Estrogen deficiency accelerates postmenopausal atherosclerosis by inducing endothelial cell ferroptosis through inhibiting NRF2/GPX4 pathway.

Abstract

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.

• Authors: Ying Lv, Shan Zhang, Xiuzhu Weng, Jianxin Huang, Honggang Zhao, Xinyu Dai, Xiaoxuan Bai, Xiaoyi Bao, Chen Zhao, Ming Zeng, Yunshu Bai, Sining Hu, Ji Li, Haibo Jia, Bo Yu
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 37 Issue 6 Pg. e22992 (06 2023) ISSN: 1530-6860 [Electronic] United States
• PMID: 37219513 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 Federation of American Societies for Experimental Biology.

Chemical References

• Estrogens
• Iron
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• glutathione peroxidase 4, mouse

Topics

• Animals
• Female
• Mice
• Atherosclerosis
• Endothelial Cells
• Estrogens (deficiency)
• Iron
• NF-E2-Related Factor 2
• Postmenopause