Resolvin D1 attenuates acid-induced DNA damage in esophageal epithelial cells and rat models of acid reflux

被引:3
|
作者
Zhao, Ye [1 ]
Ma, Teng [2 ]
Zhang, Zhihan [3 ]
Chen, Xi [1 ]
Zhou, Chunhua [1 ]
Zhang, Ling [1 ]
Zou, Duowu [1 ]
机构
[1] Shanghai Jiao Tong Univ Sch Med, Ruijin Hosp, Dept Gastroenterol, 197 Ruijin Er Rd, Shanghai 200025, Peoples R China
[2] Fudan Univ, Zhongshan Hosp, Dept Thorac Surg, Shanghai 200030, Peoples R China
[3] Shanghai Jiao Tong Univ Sch Med, Ruijin Hosp, Dept Pathol, Shanghai 200025, Peoples R China
基金
中国国家自然科学基金;
关键词
Resolvin D1; Gastroesophageal reflux disease; DNA damage; Reactive oxygen species; Oxidative stress; Acid reflux; POLYUNSATURATED FATTY-ACIDS; PTEN; CHK1; INHIBITION; EXPRESSION; MEDIATORS; RECEPTOR; DISEASE; ATR; PH;
D O I
10.1016/j.ejphar.2021.174571
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The role of resolvin D1 (RvD1) in gastroesophageal reflux disease (GERD) remains largely unknown. Here, we investigated the potential role of RvD1 in acid-induced DNA damage in esophageal epithelial cells, patients with refractory GERD and a rat model of acid reflux. Weak acid exposure induced longer comet tails, reactive oxygen species (ROS) generation, oxidative DNA damage and DNA double-strand breaks (DSBs) in cells and RvD1 (0.1 mu M) blocked all these effects. Mechanistic analyses showed that apart from ROS-reducing effects, RvD1 possessed a strong capacity to promote DNA damage repair, augmenting cell cycle checkpoint activity and DSB repair by modulating phosphatase and tensin homolog (PTEN) in cells. We also detected the surface expression of formyl peptide receptor 2 (FPR2), a receptor for RvD1, in the esophageal epithelial cells, and inhibition of FPR2 abrogated the protective effects of RvD1 on cells. Furthermore, a positive correlation between RvD1 and PTEN was observed predominantly in the esophageal epithelium from patients with refractory GERD (r = 0.67, P < 0.05). Additionally, RvD1 administration upregulated PTEN, suppressed DNA DSBs and alleviated microscopic damage in the rat model of gastric reflux. FPR2 gene silencing abolished the therapeutic effects of RvD1 on the rat model. Taken together, RvD1 binding to FPR2 protects the esophageal epithelium from acid reflux-induced DNA damage via a mechanism involving the inhibition of ROS production and facilitation of DSB repair. These findings support RvD1 as a promising approach that may be valuable for the treatment of GERD.
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页数:12
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