Hypobaric hypoxia promotes macrophage necroptosis and atherosclerotic plaque in-stability in mice
10.20039/j.cnki.1007-3949.2025.03.005
- VernacularTitle:低压低氧导致巨噬细胞坏死性凋亡和小鼠动脉粥样斑块不稳定
- Author:
Tao HU
1
;
Yingrong HE
;
Wushuai WANG
;
Xi YANG
;
Qinghua DUAN
;
Xuan DU
;
Qiang WANG
Author Information
1. 西部战区总医院心血管内科,四川省成都市 610083
- Publication Type:Journal Article
- Keywords:
hypobaric hypoxia;
adenosine deaminase acting on RNA 1;
Z-DNA binding protein 1;
macro-phage;
necroptosis;
atherosclerosis;
plaque instability
- From:
Chinese Journal of Arteriosclerosis
2025;33(3):219-226
- CountryChina
- Language:Chinese
-
Abstract:
Aim To investigate the effect of hypobaric hypoxia on macrophage necroptosis and atherosclerotic plaque instability and explore the underlying mechanisms.Methods Mouse bone marrow-derived macrophages were i-solated and cultured,and divided into control group(21％oxygen concentration)and hypoxia group(3％oxygen concen-tration).After 48 hours,cell necroptosis was detected,and the expression of cell necroptosis related proteins was deter-mined by Western blot.Healthy male ApoE-/-mice were randomly divided into control group and hypobaric hypoxia group.After the intervention for 16 weeks,the plasma lipids and inflammatory cytokines were measured,the areas of ath-erosclerotic plaque and necrotic core were evaluated by HE staining.The content of plaque collagen was detected by Mas-son staining.The number of macrophages in the plaque and the expression of necrotic apoptosis related proteins were de-tected by immunohistochemical staining and Western blot.Results Hypoxia induced increased necrotic apoptosis of macrophages(P＜0.01),while necroptotic inhibitor necrostatin-1(Nec-1)reduced hypoxia induced cell death(P＜0.05);hypoxia leads to a decrease in the expression of adenosine deaminase acting on RNA 1(ADAR1)in macrophages(P＜0.01),and an increase in the expression of Z-DNA binding protein 1(ZBP1),phosphorylated receptor-interacting serine/threonine-protein kinase(p-RIPK3),and phosphorylated mixed lineage kinase domain-like protein(p-MLKL)(all P＜0.01).Compared with the control group,the plasma lipid levels of ApoE-/-mice in the hypobaric hypoxia group did not change significantly(P＞0.05),the plasma inflammatory cytokines(TNF-α,IL-1β,IL-6 and MCP-1)increased(all P＜0.05),the area of atherosclerotic plaque increased(P＜0.05),the area of plaque necrotic core increased,the content of plaque collagen decreased,the number of macrophages increased,the expression of ADAR1 decreased,and the expres-sion of ZBP1 and p-MLKL increased(all P＜0.01).Conclusion Hypobaric hypoxia causes the imbalance of A-DAR1/ZBP1 expression in macrophages,activates RIPK3/MLKL signaling pathway,promotes macrophage necroptosis,in-creases the area of plaque necrosis core,and leads to increase instability of atherosclerotic plaque.
