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

ABSTRACT: 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 (ER?)-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 ER? 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 ER? 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 ER? expression. Thus, the results of the present study demonstrated that post-menopausal women present decreased autophagy and ER? expression and excessive damage to the ascending aorta. In addition, in vitro and in vivo assay results demonstrated that estrogen prevents atherosclerosis by upregulating ER? expression and subsequently induces autophagy to reduce inflammation and pyroptosis.

SUBMITTER: Meng Q

PROVIDER: S-EPMC7753237 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Meng Qinghai Q Li Yu Y Ji Tingting T Chao Ying Y Li Jun J Fu Yu Y Wang Suyun S Chen Qi Q Chen Wen W Huang Fuhua F Wang Youran Y Zhang Qichun Q Wang Xiaoliang X Bian Huimin H

Journal of advanced research 20200824

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 arte ...[more]

PMID: 33364052

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Project description:Majority of breast cancer specific deaths in women with ERα (+) tumor occur due to metastases that are resistant to endocrine therapy. There is a critical need for novel therapeutic approaches to resensitize recurrent ERα (+) tumors to endocrine therapies. The objective of this study was to elucidate mechanisms of improved effectiveness of combined targeting of ERα and XPO1, a nuclear transport protein in overcoming endocrine resistance. Selinexor (SXR), an XPO1 antagonist, has been evaluated in multiple later stage clinical trials in patients with relapsed and /or refractory hematological and solid tumor malignancies. Using human phosphokinase array to profile kinase signaling pathways, we found that 4-OH Tamoxifen, SXR or their combination induced differential Akt phosphorylation profiles, changing the phosphorylation status and activity of the kinase. Also, our RNA sequencing data indicated that 4-OH Tamoxifen+SXR combination treatment causes gene expression changes distinct from 4-OH Tamoxifen and SXR treatments alone in tamoxifen-resistant cell lines. Since we observed dramatic changes in Akt activity and we saw a differential gene expression pattern with individual and combined 4-OH Tamoxifen and SXR treatments, we hypothesized that metabolic profile of breast cancer cells would change in the presence of 4-OH Tamoxifen and SXR. Using Seahorse metabolic profiler and cell viability experiments in limited media conditions, we showed that tamoxifen resistant cells were more dependent on mitochondria for energy production. Their glucose and fatty acid dependency decreased in the presence of SXR and cells were more dependent on glutamine as the mitochondrial fuel source. We demonstrated that combined targeting of XPO1 and ERα rewires metabolic pathways and shuts down both glycolytic and mitochondrial pathways that would eventually lead to autophagy. Remodelling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and given the need for better strategies for improving therapy response of relapsed ERα (+) tumors, our findings show great promise for uncovering the role of ERα-XPO1 crosstalk plays in reducing cancer recurrences.

Dataset Information

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

Publications

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

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