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Autophagy blockage promotes the pyroptosis of ox-LDL-treated macrophages by modulating the p62/Nrf2/ARE axis.

ABSTRACT: Atherosclerosis, a chronic comprehensive cardiovascular disease, is characterized by the lipid infiltration, formation of foam cells derived from macrophages and inflammation in the vessel wall. Substantial evidence confirms that the activity of autophagic bodies plays a pivot role in regulating cell deaths, but the mechanisms of autophagy to regulate the pyroptosis of macrophages in atherosclerosis remain unclear. In our study, we explored that ox-LDL decreased the cell viability and destroyed the integrity of cell membrane, resulting in the pyroptosis of THP-1 derived macrophages in a dose-dependent manner. Western blotting, qRT-PCR and ELISA also showed that chloroquine (CQ) could up-regulate the expression of p62 through impairing autophagy and induce the pyroptosis of macrophages treated by ox-LDL, as evidenced by the decrease of cell viability and membrane integrity, and the increase of pro-caspase-1, GSDMD, and proinflammatory factors IL-1β and IL-18. Further researches demonstrated that Nrf2, a nuclear factor activated by p62, was linked to macrophage pyroptosis. Overactivating or suppressing Nrf2/ARE signaling would correspondingly aggravate or alleviate pyroptosis, in which the level of p62 was regulated by Nrf2 feedback. Then, bioinformatic analysis verified that there was a close interaction between p62, Nrf2/ARE signaling proteins and pyroptosis-related proteins. Taken together, our results show that blocking autophagy promotes the pyroptosis of ox-LDL-treated macrophages via the p62/Nrf2/ARE axis, providing a novel therapeutic target for atherosclerosis.

SUBMITTER: Liu J

PROVIDER: S-EPMC8060691 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Atherosclerosis (AS), a major cause of cardiovascular disease, has developed into a serious challenge to the health system. The long non?coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is associated with the pathogenesis of AS. However, whether MALAT1 can affect cholesterol accumulation in macrophages during AS progression, and the potential molecular mechanism involved in this progression have not been elucidated. In the present study, the mRNA expression level of MALAT1 was measured using reverse transcription?quantitative PCR (RT?qPCR) and the protein expression level was detected via western blot analysis. Oil Red O staining was used for detecting lipid accumulation in macrophages. Bioinformatics, dual?luciferase reporter and RT?qPCR assays were used to investigate the relationship between MALAT1 and the microRNA (miR)?17?5p/ATP?binding cassette transporter A1 (ABCA1) axis. The present results suggested that the MALAT1 expression level was significantly decreased in patients with AS and in oxidized low?density lipoprotein (ox?LDL)?stimulated macrophages. Knockdown of MALAT1 increased ox?LDL uptake, lipid accumulation and the total cholesterol (T?CHO) level in ox?LDL?induced macrophages. In addition, MALAT1 inhibition significantly decreased the mRNA and protein expression levels of scavenger receptor (SR) class B member 1, apolipoprotein E (ApoE) and ABCA1. However, MALAT1 increased the expression level of SR class A. Subsequently, the present study investigated whether MALAT1 could target miR?17?5p to regulate the expression level of ABCA1, which is involved in cholesterol efflux from macrophages. The present results suggested that inhibition of miR?17?5p reversed the effects of MALAT1 knockdown on T?CHO content, and protein expression levels of ApoE and ABCA1 in ox?LDL?stimulated macrophages. In summary, knockdown of MALAT1 may promote cholesterol accumulation by regulating the miR?17?5p/ABCA1 axis in ox?LDL?induced THP?1 macrophages.

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Autophagy blockage promotes the pyroptosis of ox-LDL-treated macrophages by modulating the p62/Nrf2/ARE axis.

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