Activation of the High Mobility Group Box 1/Receptor for Advanced Glycation Endproducts /NOD‐like Receptor Family Pyrin Domain‐Containing 3 Axis Under Chronic Intermittent Hypoxia Induction Promotes the Progression of Atherosclerosis in ApoE−/− Mice

Abstract

Background Chronic intermittent hypoxia (CIH) has been regarded as an important cause of atherosclerotic disease. In our study, we set out to investigate whether CIH regulated the high mobility group box 1/receptor for advanced glycation endproducts/NOD‐like receptor family pyrin domain‐containing 3 (HMGB1/RAGE/NLRP3) axis to affect the progression of atherosclerosis. Methods and Results Initially, peripheral blood samples were collected from patients with single obstructive sleep apnea, atherosclerosis complicated with obstructive sleep apnea, and healthy volunteers. In vitro cell experiments were conducted using human monocyte cell line THP‐1 and human umbilical vein endothelial cells to explore the role of HMGB1 in cell migration, apoptosis, adhesion, and transendothelial migration. In addition, a CIH‐induced atherosclerosis mouse model was established for further identifying the critical role of the HMGB1/RAGE/NLRP3 axis in atherosclerosis. Upregulated HMGB1 and RAGE were found in patients with atherosclerosis complicated with obstructive sleep apnea. CIH induction increased HMGB1 expression by inhibiting HMGB1 methylation, activating the RAGE/NLRP3 axis. After inhibition of the HMGB1/RAGE/NLRP3 axis, monocyte chemotaxis and adhesion were repressed, and macrophage‐derived foam cell formation was inhibited, accompanied by suppression of endothelial and foam cell apoptosis and inflammatory factor secretion. In vivo animal experiments also noted that the progression of atherosclerosis was prevented by inhibition of the HMGB1/RAGE/NLRP3 axis in CIH‐induced ApoE−/− mice. Conclusions Taken together, CIH induction can upregulate HMGB1 through inhibition of HMGB1 methylation, which activates the RAGE/NLRP3 axis to promote inflammatory factor secretion, thereby promoting the progression of atherosclerosis.

Keywords

• atherosclerosis
• chronic intermittent hypoxia
• HMGB1
• NLRP3
• promoter methylation
• RAGE