Activation of ATM-c-IAP1 Pathway Mediates the Protective Effects of Estradiol in Human Vascular Endothelial Cells Exposed to Intermittent Hypoxia
Received 18 September 2019
Accepted for publication 5 November 2019
Published 28 November 2019 Volume 2019:11 Pages 357—366
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 2
Editor who approved publication: Professor Steven A Shea
Ying Ni Lin,1,2,* Xiao Fei Lan,1,3,* Zhuo Ran Liu,4,* Ya Ru Yan,1,2 Jian Ping Zhou,1,2 Ning Li,1,2 Xian Wen Sun,1,2 Qing Yun Li1,2
1Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People’s Republic of China; 2Institute of Respiratory Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People’s Republic of China; 3Department of Respiratory Medicine, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200335, People’s Republic of China; 4Department of Thyroid and Vascular Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Qing Yun Li
Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People’s Republic of China
Purpose: Chronic intermittent hypoxia (CIH) contributes to the increased risk of cardiovascular diseases in obstructive sleep apnea (OSA). We previously reported the anti-apoptotic effects of estradiol (E2) on IH-exposed human umbilical vein endothelial cells (HUVECs). Herein, we employed a proteomic analysis to elucidate the mechanisms of the protective effects of E2 under IH exposure.
Methods: HUVECs were divided into three groups: control, IH, and IH+E2 group. Isobaric tags for relative and absolute quantification (iTRAQ) were performed to compare protein profiles among the groups. Some of the identified proteins were validated by Western blotting.
Results: A total of 185 proteins were differentially expressed in the IH+E2 group compared to the IH group. Bioinformatics analysis indicated that the effects of E2 may be linked to the regulation of cellular stress response. Among the differentially expressed proteins, we identified that serine-protein kinase ataxia telangiectasia mutated (ATM) and its downstream target, cellular inhibitor of apoptosis protein 1 (c-IAP1), were up-regulated by E2. We also observed that E2 decreased the level of cleaved caspase-3 and inhibited cell apoptosis in IH-exposed HUVECs. The inhibition of ATM abolished the anti-apoptotic effect of E2.
Conclusion: The ATM-c-IAP1 pathway is involved in the cardioprotective effects of E2 in HUVECs exposed to IH.
Keywords: estradiol, obstructive sleep apnea, OSA, intermittent hypoxia, IH, endothelial dysfunction, proteomics
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