Aldehyde dehydrogenase 2 inhibited oxidized LDL-induced NLRP3 inflammasome priming and activation via attenuating oxidative stress

Youshun Xu; Qiaozhen Yuan; Shengchuan Cao; Sumei Cui; Li Xue; Xin Song; Zheng Li; Rong Xu; Qiuhuan Yuan; Ruijian Li

doi:10.1016/j.bbrc.2020.06.075

Aldehyde dehydrogenase 2 inhibited oxidized LDL-induced NLRP3 inflammasome priming and activation via attenuating oxidative stress

Biochem Biophys Res Commun. 2020 Sep 3;529(4):998-1004. doi: 10.1016/j.bbrc.2020.06.075. Epub 2020 Jul 30.

Authors

Youshun Xu¹, Qiaozhen Yuan², Shengchuan Cao³, Sumei Cui³, Li Xue³, Xin Song⁴, Zheng Li⁴, Rong Xu⁵, Qiuhuan Yuan⁶, Ruijian Li⁷

Affiliations

¹ Department of Emergency, Qilu Hospital, Shandong University, Jinan, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Shandong University, Jinan, China; Key Laboratory of Cardiovascular Remodeling & Function Research, Chinese Ministry of Education & Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, China; School of Medicine, Shandong University, Jinan, China.
² Department of Cardiology, Ju-ye People's Hospital, Heze, China.
³ Department of Emergency, Qilu Hospital, Shandong University, Jinan, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Shandong University, Jinan, China; Key Laboratory of Cardiovascular Remodeling & Function Research, Chinese Ministry of Education & Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, China.
⁴ Department of Emergency, Qilu Hospital, Shandong University, Jinan, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Shandong University, Jinan, China; Key Laboratory of Cardiovascular Remodeling & Function Research, Chinese Ministry of Education & Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, China; School of Basic Medicine, Shandong University, Jinan, China.
⁵ School of Medicine, Shandong University, Jinan, China.
⁶ Department of Emergency, Qilu Hospital, Shandong University, Jinan, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Shandong University, Jinan, China; Key Laboratory of Cardiovascular Remodeling & Function Research, Chinese Ministry of Education & Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, China. Electronic address: xiaoqiu0707@aliyun.com.
⁷ Department of Emergency, Qilu Hospital, Shandong University, Jinan, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Shandong University, Jinan, China; Key Laboratory of Cardiovascular Remodeling & Function Research, Chinese Ministry of Education & Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, China. Electronic address: liruijian2003@sdu.edu.cn.

PMID: 32819611
DOI: 10.1016/j.bbrc.2020.06.075

Abstract

Oxidized low-density lipoprotein (ox-LDL)-mediated NLRP3 inflammasome activation is crucial in atherosclerosis (AS) initiation and progression. Aldehyde dehydrogenase 2 (ALDH2) has been reported to display protective effects during AS development; however, the underlying mechanisms are largely unknown. Here we investigate the role of ALDH2 in ox-LDL-induced NLRP3 inflammasome priming and activation. We treated RAW264.7 murine macrophages with ox-LDL with or without ALDH2 activator Alda-1 and measured NLRP3 inflammasome priming and activation, ALDH2 protein expression and enzyme activity, IL-1β release, and DNA damage. It was found that ox-LDL impaired ALDH2 activity and induced NLRP3 inflammasome priming and activation. Alda-1 inhibited both of the priming and activation steps of NLRP3 inflammasome as well as subsequent cell pyroptosis and attenuated ROS and 4-HNE levels in ox-LDL-treated macrophages. Taken together, ALDH2 activation inhibits priming and activation of NLRP3 inflammasome via reducing oxidative stress, which suggests that ALDH2 may be a potential target for anti-inflammatory therapies in AS treatment.

Keywords: Aldehyde dehydrogenase 2; Atherosclerosis; NLRP3 inflammasome; Oxidative stress; Pyroptosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aldehyde Dehydrogenase, Mitochondrial / genetics*
Aldehyde Dehydrogenase, Mitochondrial / metabolism
Aldehydes / antagonists & inhibitors
Aldehydes / metabolism
Animals
Anti-Inflammatory Agents / pharmacology*
Benzamides / pharmacology*
Benzodioxoles / pharmacology*
Caspase 1 / genetics
Caspase 1 / metabolism
DNA Damage
Gene Expression Regulation
Humans
Inflammasomes / drug effects*
Inflammasomes / metabolism
Interleukin-1beta / antagonists & inhibitors
Interleukin-1beta / genetics
Interleukin-1beta / metabolism
Lipoproteins, LDL / antagonists & inhibitors*
Lipoproteins, LDL / pharmacology
Mice
NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors
NLR Family, Pyrin Domain-Containing 3 Protein / genetics*
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Oxidative Stress / drug effects
Pyroptosis / drug effects
Pyroptosis / genetics
RAW 264.7 Cells
Reactive Oxygen Species / antagonists & inhibitors
Reactive Oxygen Species / metabolism
Signal Transduction

Substances

Aldehydes
Anti-Inflammatory Agents
Benzamides
Benzodioxoles
IL1B protein, mouse
Inflammasomes
Interleukin-1beta
Lipoproteins, LDL
N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Reactive Oxygen Species
oxidized low density lipoprotein
ALDH2 protein, mouse
Aldehyde Dehydrogenase, Mitochondrial
Caspase 1
4-hydroxy-2-nonenal