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EETs alleviate alveolar epithelial cell senescence by inhibiting endoplasmic reticulum stress through the Trim25/Keap1/Nrf2 axis

Authors :
Chen-Yu Zhang
Wen-Jing Zhong
Yu-Biao Liu
Jia-Xi Duan
Nan Jiang
Hui-Hui Yang
Sheng-Chao Ma
Ling Jin
Jie-Ru Hong
Yong Zhou
Cha-Xiang Guan
Source :
Redox Biology, Vol 63, Iss , Pp 102765- (2023)
Publication Year :
2023
Publisher :
Elsevier, 2023.

Abstract

Alveolar epithelial cell (AEC) senescence is a key driver of a variety of chronic lung diseases. It remains a challenge how to alleviate AEC senescence and mitigate disease progression. Our study identified a critical role of epoxyeicosatrienoic acids (EETs), downstream metabolites of arachidonic acid (ARA) by cytochrome p450 (CYP), in alleviating AEC senescence. In vitro, we found that 14,15-EET content was significantly decreased in senescent AECs. Exogenous EETs supplementation, overexpression of CYP2J2, or inhibition of EETs degrading enzyme soluble epoxide hydrolase (sEH) to increase EETs alleviated AECs' senescence. Mechanistically, 14,15-EET promoted the expression of Trim25 to ubiquitinate and degrade Keap1 and promoted Nrf2 to enter the nucleus to exert an anti-oxidant effect, thereby inhibiting endoplasmic reticulum stress (ERS) and alleviating AEC senescence. Furthermore, in D-galactose (D-gal)-induced premature aging mouse model, inhibiting the degradation of EETs by Trifluoromethoxyphenyl propionylpiperidin urea (TPPU, an inhibitor of sEH) significantly inhibited the protein expression of p16, p21, and γH2AX. Meanwhile, TPPU reduced the degree of age-related pulmonary fibrosis in mice. Our study has confirmed that EETs are novel anti-senescence substances for AECs, providing new targets for the treatment of chronic lung diseases.

Details

Language :
English
ISSN :
22132317
Volume :
63
Issue :
102765-
Database :
Directory of Open Access Journals
Journal :
Redox Biology
Publication Type :
Academic Journal
Accession number :
edsdoj.408c188596b14c6ca33e3bf3255d2f78
Document Type :
article
Full Text :
https://doi.org/10.1016/j.redox.2023.102765