雌激素缺乏通过抑制 NRF2/GPX4 通路诱导内皮细胞铁死亡加速绝经后动脉粥样硬化,The FASEB Journal

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雌激素缺乏通过抑制 NRF2/GPX4 通路诱导内皮细胞铁死亡加速绝经后动脉粥样硬化
The FASEB Journal ( IF 4.4 ) Pub Date : 2023-05-23 , DOI: 10.1096/fj.202300083r
Ying Lv _{1,

2} , Shan Zhang _{1,

2} , Xiuzhu Weng _{1,

2} , Jianxin Huang _{1,

2} , Honggang Zhao _{1,

2} , Xinyu Dai _{1,

2} , Xiaoxuan Bai _{1,

2} , Xiaoyi Bao _{1,

2} , Chen Zhao _{1,

2} , Ming Zeng _{1,

2} , Yunshu Bai ₃ , Sining Hu _{1,

2} , Ji Li _{1,

2} , Haibo Jia _{1,

2} , Bo Yu _{1,

2}

Affiliation

雌激素缺乏引起的氧化应激和脂质代谢紊乱被认为是绝经后动脉粥样硬化的主要原因，但其机制仍不清楚。在这项研究中，切除卵巢 (OVX) 的女性 ApoE ^−/−用高脂肪饮食喂养的小鼠被用来模拟绝经后动脉粥样硬化。OVX 小鼠的动脉粥样硬化进展明显加速，伴随着铁死亡指标的上调，包括斑块和血浆中脂质过氧化和铁沉积的增加。雌二醇 (E2) 和铁死亡抑制剂 ferrostatin-1 均能减轻 OVX 小鼠的动脉粥样硬化，抑制脂质过氧化和铁沉积，并上调 xCT 和 GPX4，尤其是在内皮细胞中。我们进一步研究了 E2 对氧化低密度脂蛋白或铁死亡诱导剂 Erastin 诱导的内皮细胞铁死亡的影响。发现E2通过抗氧化功能表现出抗铁死亡的作用，包括改善线粒体功能障碍和上调 GPX4 表达。从机制上讲，NRF2 抑制减弱了 E2 对铁死亡的作用以及 GPX4 的上调。我们的研究结果表明，内皮细胞铁死亡在绝经后动脉粥样硬化进展中起着关键作用，NRF2/GPX4 通路激活有助于保护 E2 免受内皮细胞铁死亡。

"点击查看英文标题和摘要"

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

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.

更新日期：2023-05-23

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