Excessive inflammation and the pyroptosis of vascular endothelial cells caused by estrogen deficiency is one cause of atherosclerosis in post-menopausal women. Because autophagy is highly regulated by estrogen, we hypothesized that estrogen can reduce vascular endothelial cell pyroptosis through estrogen receptor alpha (ERα)-mediated activation of autophagy to improve atherosclerosis in post-menopausal stage. Aortic samples from pro-menopausal and post-menopausal women with ascending aortic arteriosclerosis were analyzed, and bilateral ovariectomized (OVX) female ApoE-/- mice and homocysteine (Hcy)-treated HUVECs were used to analyze the effect of estrogen supplementation therapy. The aortic endothelium showed a decrease in ERα expression and autophagy, but presented an increase in inflammation and pyroptosis in female post-menopausal patients. Estrogen treatment accelerated autophagy and ameliorated cell pyroptosis in the cardiac aortas of OVX ApoE-/- mice and Hcy-treated HUVECs. Estrogen had therapeutic effect on atherosclerosis and improved the symptoms associated with lipid metabolism disorders in OVX ApoE-/- mice. Inhibition and silencing of ERα led to a reduction in the autophagy promoting ability of estrogen and aggravated pyroptosis. Moreover, the inhibition of autophagy promoted pyroptosis and abolished the protective effect of estrogen, but had no influence on ERα expression. Thus, the results of the present study demonstrated that post-menopausal women present decreased autophagy and ERα expression and excessive damage to the ascending aorta. In addition, in vitro and in vivo assay results demonstrated that estrogen prevents atherosclerosis by upregulating ERα expression and subsequently induces autophagy to reduce inflammation and pyroptosis.

雌激素缺乏引起的过度炎症和血管内皮细胞焦亡是绝经后妇女动脉粥样硬化的原因之一。由于自噬受到雌激素的高度调节，我们推测雌激素可以通过雌激素受体α（ERα）介导的自噬激活来减少血管内皮细胞焦亡，从而改善绝经后阶段的动脉粥样硬化。对患有升主动脉硬化的绝经前和绝经后女性的主动脉样本进行了分析，并使用双侧卵巢切除（OVX）雌性 ApoE-/- 小鼠和同型半胱氨酸（Hcy）处理的 HUVEC 来分析雌激素补充疗法的效果。女性绝经后患者的主动脉内皮表现出 ERα 表达和自噬减少，但炎症和细胞焦亡增加。雌激素治疗可加速 OVX ApoE-/- 小鼠和 Hcy 处理的 HUVEC 心脏主动脉的自噬并改善细胞焦亡。雌激素对OVX ApoE-/-小鼠的动脉粥样硬化具有治疗作用，并改善与脂质代谢紊乱相关的症状。 ERα的抑制和沉默导致雌激素促进自噬的能力降低，细胞焦亡加剧。此外，抑制自噬促进焦亡并消除雌激素的保护作用，但对 ERα 表达没有影响。因此，本研究的结果表明，绝经后女性存在自噬和 ERα 表达下降以及升主动脉过度损伤。 此外，体外和体内测定结果表明，雌激素通过上调 ERα 表达来预防动脉粥样硬化，并随后诱导自噬以减少炎症和细胞焦亡。