Estradiol Regulates Txnip and Prevents Intermittent Hypoxia-Induced Vascular Injury

Abstract

Chronic intermittent hypoxia (IH) contributes to obstructive sleep apnea (OSA)-related cardiovascular diseases through increasing oxidative stress. It has been widely recognized that estradiol decreases the risk for cardiovascular disease, but the estrogen replacement therapy is limited for its side effects. Thioredoxin (Trx) and its endogenous inhibitor, thioredoxin-interacting protein (Txnip), are associated with the protective effect of estradiol in some conditions. In this study, we aimed to explore whether estradiol could protect against IH-induced vascular injury, and the possible effect of Trx-1/Txnip in this process. Forty-eight adult female C57/BL6J mice were randomly divided into 4 groups, ovariectomy combined with IH group, sham operation combined with IH group, IH group and the control group. The mice treated with IH for 8 hrs/day, and 28 days. IH induced the injury of aorta, and ovariectomized mice were more prone to the IH-induced aortic injury, with higher level of oxidative stress. In vitro, estradiol increased Trx-1 level, but decreased the level of Txnip and oxidative stress in human umbilical vein endothelial cells (HUVECs) treated with IH for 16 hrs. Knock-down of Txnip by specific siRNA rescued oxidative stress and apoptosis. In conclusion, estradiol protects against IH-induced vascular injury, partially through the regulation of Trx-1/Txnip pathway.

<p>Activation of ATM-c-IAP1 Pathway Mediates the Protective Effects of Estradiol in Human Vascular Endothelial Cells Exposed to Intermittent Hypoxia</p>

“…We previously found that E2 suppressed oxidative stress and decreased cell apoptosis in IH-exposed HUVECs 9. In this study, a group of differentially expressed proteins between the IH and IH+E2 group were involved in cellular stress response (such as DNA damage and heat response) based on functional analysis.…”

“…CIH induces oxidative stress,9,24 and consequently causes oxidative DNA damage and cytotoxicity, leading to endothelial cell apoptosis. In the study, we exposed HUVECs to 1% O 2 for 5 mins followed by 5 mins at 21% O 2 in the gas phase (equivalent to 6 cycles/hr).…”

“…A proteomic analysis of vascular wall of male and female mice under CIH revealed a sex difference in the expressions of inflammation-related proteins, lipid metabolism-related proteins, and renin-binding protein 8. Additionally, we previously found that ovariectomized mice were more prone to the CIH-induced vascular injury than the sham-operated ones, and also observed that estradiol (E2) decreased IH-induced oxidative stress and cell apoptosis in human umbilical vein endothelial cells (HUVECs) 9. However, the molecular mechanisms of the protective effects of E2 on IH-induced endothelial injury are still poorly understood.…”

Gene expression profiles of glucose toxicity‐exposed islet microvascular endothelial cells

“…And moreover, MMP13 could increase the secretion of VEGF‐A from endothelial cells, by which it may directly promote angiogenesis and capillary formation and is well correlated with microvascular density. In addition, studies indicated that some mRNAs, such as TXNIP and VCAM‐1 played a pivotal role in glucose toxicity‐induced oxidative effects, microvascular injury, and endothelial dysfunction. Collectively, these gene expression profiles that relating with microvascular endothelial cells function exhibit a substantial changing trend in glucose toxicity exposure, supporting the view that their up‐ and downregulation may be involved in the impairment of IMECs.…”

Estrogen Modulates the Sensitivity of Lung Vagal C Fibers in Female Rats Exposed to Intermittent Hypoxia

“…In addition, estrogen can modulate the immune function of various cell types ( Straub, 2007 ) and possibly interferes with the production of various cytokines, such as interleukin-1β (IL-1β), NF-κB, and tumor necrosis factor-α (TNF-α) in several systems ( Stein and Yang, 1995 ; Cerillo et al, 1998 ; Evans et al, 2002 ; Sarvari et al, 2011 ). Although estrogen is a critical contributor to gender effects on OSA-associated cardiovascular consequences ( Kapsimalis and Kryger, 2002 ; Lan et al, 2017 ), its role in the development of OSA-related hyperreactive airway diseases in females remains unclear.…”