Di’ao Xinxuekang Capsule Improves the Anti-Atherosclerotic Effect of Atorvastatin by Downregulating the SREBP2/PCSK9 Signalling Pathway

Abstract

Statins are the first choice for lowering low-density lipoprotein cholesterol (LDL-C) and preventing atherosclerotic cardiovascular disease (ASCVD). However, statins can also upregulate proprotein convertase subtilisin/kexin type 9 (PCSK9), which in turn might limits the cholesterol-lowering effect of statins through the degradation of LDL receptors (LDLR). Di’ao Xinxuekang (DXXK) capsule, as a well-known traditional Chinese herbal medicine for the prevention and treatment of coronary heart disease, can alleviate lipid disorders and ameliorate atherosclerosis in atherosclerosis model mice and downregulate the expression of PCSK9. In this study, we further explored whether DXXK has a synergistic effect with atorvastatin (ATO) and its underlying molecular mechanism. The results showed that both ATO monotherapy (1.3 mg/kg) and ATO combined with DXXK therapy significantly lowered serum lipid levels and reduced the formation of atherosclerotic plaques and the liver lipid accumulation. Moreover, compared with ATO monotherapy, the addition of DXXK (160 mg/kg) to the combination therapy further lowered LDL-C by 15.55% and further reduced the atherosclerotic plaque area by 25.98%. In addition, the expression of SREBP2, PCSK9 and IDOL showed a significant increase in the model group, and the expression of LDLR was significantly reduced; however, there were no significant differences between the ATO (1.3 mg/kg) and the model groups. When ATO was combined with DXXK, the expression of LDLR was significantly increased and was higher than that of the model group and the expression of SREBP2 and PCSK9 in the liver was also significantly inhibited. Moreover, it can be seen that the expression of SREBP2 and PCSK9 in the combination treatment group was significantly lower than that in the ATO monotherapy group (1.3 mg/kg). Besides, the expression of IDOL mRNA in each treatment group was not significantly different from that of the model group. Our study suggests that DXXK might have a synergistic effect on the LDL-C lowering and antiatherosclerosis effects of ATO through the SREBP2/PCSK9 pathway. This indicates that a combination of DXXK and ATO may be a new treatment for atherosclerosis.

Effects of Atorvastatin on Bile Acid Metabolism in High-fat Diet–fed ApoE−/− Mice

“…After 20 weeks of high-fat diet feeding, the model mice not only showed significantly higher serum levels of TC, TG, and LDL-C and a lower serum level of HDL-C but also formulated atherosclerotic plaques in the aorta and had obvious liver steatosis. ATO treatment (1.3 and 10 mg/kg) significantly alleviated hyperlipidemia and atherosclerotic lesions to varying degrees, which was consistent with the study by Liang et al 20 It is generally believed that statins lower LDL-C level mainly by inhibiting the endogenous cholesterol synthesis and subsequently upregulating the effect of LDLR. We also found that ATO could increase LDLR expression in this study.…”

Quinic acid regulated TMA/TMAO-related lipid metabolism and vascular endothelial function through gut microbiota to inhibit atherosclerotic

“…6 A). Previous studies have shown that the LXR-IDOL-LDLR feedback [ 26 ], the SREBP2/PCSK9 pathway [ 27 ], and liver FMO3 expression [ 28 ] mediate the liver lipid, cholesterol, and TMAO metabolism levels in atherosclerosis. Our study determined that HFD decreased the expression of SREBP-2 and LDLR, and increased the expression of IDOL, FMO3 and PCSK9 in the liver tissue of Apoe−/− mice (Fig.…”