Pretreatment with the ALDH2 activator Alda‑1 protects rat livers from ischemia/reperfusion injury by inducing autophagy

Liu,Zhongzhong; Ye,Shaojun; Zhong,Xiang; Wang,Wei; Lai,Chin‑Hui; Yang,Wang; Yue,Pengpeng; Luo,Jun; Huang,Xiaoying; Zhong,Zibiao; Xiong,Yan; Fan,Xiaoli; Li,Ling; Wang,Yanfeng; Ye,Qifa

doi:10.3892/mmr.2020.11312

Pretreatment with the ALDH2 activator Alda‑1 protects rat livers from ischemia/reperfusion injury by inducing autophagy

Authors:
- Zhongzhong Liu
- Shaojun Ye
- Xiang Zhong
- Wei Wang
- Chin‑Hui Lai
- Wang Yang
- Pengpeng Yue
- Jun Luo
- Xiaoying Huang
- Zibiao Zhong
- Yan Xiong
- Xiaoli Fan
- Ling Li
- Yanfeng Wang
- Qifa Ye
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Affiliations: Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China, Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nangchang, Jiangxi 330006, P.R. China
Published online on: July 8, 2020 https://doi.org/10.3892/mmr.2020.11312
Pages: 2373-2385
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Hepatic ischemia/reperfusion injury (HIRI) is a complex pathophysiological process that often leads to poor clinical prognosis. Clinically, the effective means to alleviate HIRI are limited. The aim of the present study was to investigate whether Alda‑1, an activator of mitochondrial aldehyde dehydrogenase 2 (ALDH2), had a protective effect on HIRI and to investigate the mechanisms underlying this protective effect. Sprague‑Dawley rats were treated with Alda‑1 or Daidzin, an ALDH2 inhibitor, 30 min before partial (70%) warm liver ischemia to induce HIRI. The 48 rats were randomly divided into four groups: Sham, ischemia injury (IR), IR‑Alda‑1, and IR‑Daidzin. After 6 and 24 h of reperfusion, serum and liver tissue samples were collected and stored for further experiments. Alanine aminotransferase, aspartate aminotransferase and hematoxylin & eosin staining was used to evaluate the liver damage. Western blotting and reverse transcription‑quantitative PCR were used to detect the expression of related proteins and mRNA. TUNEL staining was used to observe the apoptosis of liver cells. Transmission electron microscopy was used to detect the mitochondrial injuries. Alda‑1 pretreatment ameliorated the HIRI‑induced damage to the liver function and reduced histological lesions. Alda‑1 also increased ALDH2 activity after HIRI. Moreover, the pretreatment with Alda‑1 reduced the accumulation of toxic aldehyde 4‑hydroxy‑2‑nonenal, decreased the production of reactive oxygen species and malondialdehyde, reversed the damage to the liver mitochondria, attenuated hepatocyte apoptosis and inhibited the HIRI‑induced inflammatory response, including high‑mobility group box 1/toll‑like receptor 4 signaling. Alda‑1 also induced autophagy by upregulating autophagy‑related 7 and Rab7 increasing the microtubule associated protein 1 light chain 3 αII/I ratio and inhibiting p62 expression. ALDH2‑induced autophagy was dependent on the activation of the AKT/mammalian target of rapamycin (mTOR) and AMP‑activated protein kinase (AMPK) signaling pathways. In conclusion, the findings of the present study suggested that Alda‑1 may protect the liver against HIRI‑induced damage, including hepatic enzyme injury, acetaldehyde accumulation, oxidative stress, hepatocyte apoptosis and inflammation. Alda‑1 may confer this protection by inducing autophagy through the AKT/mTOR and AMPK signaling pathways. Therefore, ALDH2 could represent a potential pharmacological target in the clinical treatment of HIRI.

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