Berberine activates macrophage autophagy and improves atherosclerotic plaque vulnerability
LIU Qin, YANG Li-xing, SHI Jing, HUANG Yu-qing, GAO Hong-ting, JU Rui, GUO Lei
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Objective To explore the effect of berberine (BBR) on the vulnerability of atherosclerotic plaques caused by hyperglycemia and hyperlipidemia, and to discover the potential mechanism. Methods Male ApoE-/-mice were randomly divided into the control group, hyperglycemia group (intraperitoneal injection of streptozotocin(STZ), a dose of 45 mg/(kg·d) for 5 consecutive days), and hyperlipidemia group (high-fat diet, HFD). After two weeks, 10 mice were randomly selected from the hyperglycemia group to form a drug prevention group[gavage, BBR 50 mg/(kg·d)].Four weeks after modeling,the animals in the hyperglycemia model group were randomly divided into the model (STZ) group (gavage, solvent), BBR25, 50, and 100 (STZ) group (gavage, different doses of berberine [25, 50, and 100 mg/(kg·d)], the atorvastatin group [gavage, 2.5 mg/(kg·d)], the englitazone group [gavage, 1.25 mg/(kg·d)], and the hyperlipidemia model group were randomly divided into the model (HFD) group (gavage, solvent), BBR50 (HFD) group [gavage, berberine 50 mg/(kg·d)]. After 6 weeks of continuous treatment, the aorta of the mouse was taken for pathological and immunohistological examination to evaluate the atherosclerotic plaque lesions and their vulnerability index; Thp1 cells were stimulated to differentiate into macrophages with phorbol ester (PMA) and were used to investigate the effect of berberine on autophagy and inflammatory signaling pathways; Western blot was conducted to detect the expression of MIF, as well as NLRP3, AMPK/mTOR signal pathway and autophagy-related protein level in mouse aorta and cells.ELISA was used to detect the level of IL-1β in serum and cell supernatant. Results Compared with the control group, the atherosclerotic lesions in the hyperglycemia and hyperlipidemia groups were worsened, and the plaque vulnerability index was significantly increased. After the treatment with berberine, the plaque lesions were significantly improved, and the plaque vulnerability index decreased significantly(P＜0.05).Berberine down-regulated MIF protein expression in mouse aortic tissue homogenated and Thp1 cells, promoted AMPK activation, inhibited mTOR phosphorylation, regulated autophagy-related protein expression (LC3Ⅱ/LC3Ⅰ ratio increased, SQSTM1/P62 decreased), and down-regulated NLRP3 and IL-1β expression. Conclusions Berberine can effectively inhibit formation of atherosclerotic plaque and its vulnerability in ApoE-/-mice caused by hyperglycemia and hyperlipidemia. The mechanism may be attributed to the down-regulation of MIF protein expression and the promotion of autophagy of macrophages through the AMPK/mTOR signaling pathway to inhibit the inflammatory response.