Estrogen prevent atherosclerosis by attenuating endothelial cell pyroptosis via activation of estrogen receptor α-mediated autophagy

Introduction: Excessive inflammation and the pyroptosis of vascular endothelial cells caused by estrogen deficiency is one cause of atherosclerosis in post-menopausal women. The autophagy is highly regulated by estrogen, however whether estrogen can reduce vascular endothelial cell pyroptosis through estrogen receptor-mediated activation of autophagy to improve atherosclerosis in post-menopausal stage is still unknown. Objectives: To explore whether estrogen can prevent atherosclerosis by regulating estrogen receptor and subsequently activating autophagy to reduce inflammation and pyroptosis. Methods: 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. Results: The aortic endothelium showed a decrease in ER alpha 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 Hcytreated HUVECs. Estrogen had therapeutic effect on atherosclerosis and improved the symptoms associated with lipid metabolism disorders in OVX ApoE-/- mice. Inhibition and silencing of ERa 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 ERa expression. Conclusion: The results of the present study demonstrated that post-menopausal women present decreased autophagy and ER alpha expression and excessive damage to the ascending aorta. In addition, in vitro and in vivo assay results demonstrated that estrogen prevents atherosclerosis by upregulating ERa expression and subsequently induces autophagy to reduce inflammation and pyroptosis. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of Cairo University.

Automated summary

The study found that post-menopausal women have decreased autophagy and ER alpha expression in the aortic endothelium, with increased inflammation and pyroptosis. Estrogen treatment can accelerate autophagy and improve cell pyroptosis in OVX ApoE-/- mice and Hcy-treated HUVECs. Estrogen prevents atherosclerosis by upregulating ERα expression and subsequently inducing autophagy to reduce inflammation and pyroptosis.