Oridonin attenuates atherosclerosis by inhibiting foam macrophage formation and inflammation through FABP4/PPARγ signalling

• Published in: Journal of cellular and molecular medicine 2023-12, Vol.27 (24), p.4155-4170
• Main Authors: Zhang, Ming, Hou, Lianjie, Tang, Wanying, Lei, Weixing, Lin, Huiling, Wang, Yu, Long, Haijiao, Lin, Shuyun, Chen, Zhi, Wang, Guangliang, Zhao, Guojun
• Format: Article
• Language: English
• Subjects: ABCA1 protein; Antibodies; Apolipoprotein E; Arteriosclerosis; Atherosclerosis; ATP-binding protein; Cardiovascular diseases; Cholesterol; Cytokines; FABP4; Fatty acid-binding protein; Hypotheses; Inflammation; inflammatory response; Laboratory animals; lipid accumulation; Lipids; Liver X receptors; Macrophages; Molecular modelling; NF-κB protein; oridonin; Original; Peroxisome proliferator-activated receptors; PPARγ; Risk factors; Sequence analysis
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.18000

Both lipid accumulation and inflammatory response in lesion macrophages fuel the progression of atherosclerosis, leading to high mortality of cardiovascular disease. A therapeutic strategy concurrently targeting these two risk factors is promising, but still scarce. Oridonin, the bioactive medicinal compound, is known to protect against inflammatory response and lipid dysfunction. However, its effect on atherosclerosis and the underlying molecular mechanism remain elusive. Here, we showed that oridonin attenuated atherosclerosis in hyperlipidemic ApoE knockout mice. Meanwhile, we confirmed the protective effect of oridonin on the oxidized low‐density lipoprotein (oxLDL)‐induced foam macrophage formation, resulting from increased cholesterol efflux, as well as reduced inflammatory response. Mechanistically, the network pharmacology prediction and further experiments revealed that oridonin dramatically facilitated the expression of peroxisome proliferator‐activated receptor gamma (PPARγ), thereby regulating liver X receptor‐alpha (LXRα)‐induced ATP‐binding cassette transporter A1 (ABCA1) expression and nuclear factor NF‐kappa‐B (NF‐κB) translocation. Antagonist of PPARγ reversed the cholesterol accumulation and inflammatory response mediated by oridonin. Besides, RNA sequencing analysis revealed that fatty acid binding protein 4 (FABP4) was altered responding to lipid modulation effect of oridonin. Overexpression of FABP4 inhibited PPARγ activation and blunted the benefit effect of oridonin on foam macrophages. Taken together, oridonin might have potential to protect against atherosclerosis by modulating the formation and inflammatory response in foam macrophages through FABP4/PPARγ signalling.