2. Academic Validation
  3. EETs alleviate alveolar epithelial cell senescence by inhibiting endoplasmic reticulum stress through the Trim25/Keap1/Nrf2 axis

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

  • Redox Biol. 2023 Jul:63:102765. doi: 10.1016/j.redox.2023.102765.
Chen-Yu Zhang 1,  Wen-Jing Zhong 1,  Yu-Biao Liu 1,  Jia-Xi Duan 2,  Nan Jiang 1,  Hui-Hui Yang 1,  Sheng-Chao Ma 3,  Ling Jin 1,  Jie-Ru Hong 1,  Yong Zhou 4,  Cha-Xiang Guan 5
Affiliations

Affiliations

  • 1 Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, Hunan, 410078, China.
  • 2 Department of Geriatrics, Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410078, China.
  • 3 NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, 750004, China; The School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China.
  • 4 Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, Hunan, 410078, China. Electronic address: [email protected].
  • 5 Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, Hunan, 410078, China. Electronic address: [email protected].
PMID: 37269686 DOI: 10.1016/j.redox.2023.102765
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.

Keywords

Alveolar epithelial cells; Endoplasmic reticulum stress; Epoxyeicosatrienoic acids; Senescence; Tripartite motif-containing 25.

Figures
Products
Inhibitors & Agonists
Other Products