Improvement of Endothelial Dysfunction of Berberine in Atherosclerotic Mice and Mechanism Exploring through TMT-Based Proteomics

Atherosclerosis is a multifactorial vascular disease triggered by disordered lipid metabolism, characterized by chronic inflammatory injury, and initiated by endothelial dysfunction. Berberine is the main active alkaloid of the herbal medicine Coptidis Rhizoma (Huanglian). Notably, berberine has been shown to have beneficial effects against atherosclerosis. However, the mechanisms of berberine in preventing atherosclerosis are still unclear. This study is aimed at investigating the effects and mechanisms of berberine in protecting the aorta and ameliorating atherosclerosis in apolipoprotein E-deficient (ApoE(−/−)) mice. Here, we demonstrated that berberine reduced serum lipid levels, antagonized hepatic lipid accumulation, improved intima-media thickening, and alleviated atherosclerotic lesions in ApoE(−/−) mice fed a western-type diet for 12 weeks. Meanwhile, berberine reduced aortic reactive oxygen species (ROS) generation and reduced the serum levels of malondialdehyde (MDA), oxidized low-density lipoprotein (ox-LDL), and interleukin-6 (IL-6). In aortic ring assay, berberine restored aortic endothelium-dependent vasodilatation in vivo and in vitro. Furthermore, 4,956 proteins were identified by proteomic analysis, and 199 differentially expressed proteins regulated by berberine were found to be involved in many biological pathways, such as mitochondrial dysfunction, fatty acid β-oxidation I, and FXR/RXR activation. Summarily, these data suggested that berberine ameliorates endothelial dysfunction and protects against atherosclerosis, and thus may be a promising therapeutic candidate for atherosclerosis.