Abstract
Numerous risk factors are responsible for the development of atherosclerosis, for which an increased serum level of low-density lipoprotein cholesterol (LDL-C) is a driving force. By binding to the low-density lipoprotein cholesterol receptor (LDLR) and inducing LDLR degradation, proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis regulation. The inducement of PCSK9 expression is also an important reason for statin intolerance. The Di’ao Xinxuekang (DXXK) capsule extracted from Dioscorea nipponica Makino is a well-known traditional Chinese herbal medicinal product used in atherosclerotic cardiovascular disease. Although DXXK has been widely used in atherosclerotic cardiovascular treatment for nearly 30 years, studies on the potential mechanisms of the lipid-lowering effect are very limited. The purpose of the present study was to demonstrate the possible involvement of the PCSK9/LDLR signaling pathway in the lipid-lowering and antiatherosclerotic effect of DXXK in high-fat diet-fed ApoE–/– mice. The results showed that DXXK treatment alleviated hyperlipidemia, fat accumulation, and atherosclerosis formation in ApoE–/– mice. Furthermore, changes in the expression of PCSK9 mRNA in liver tissue and the circulating PCSK9 level in ApoE–/– mice were both reversed after DXXK treatment, and upregulation of LDLR in the liver was also detected in the protein level in DXXK-treated mice. Our study is the first to show that DXXK could alleviate lipid disorder and ameliorate atherosclerosis with downregulation of the PCSK9 in high-fat diet-fed ApoE–/– mice, suggesting that DXXK may be a potential novel therapeutic treatment and may support statin action in the treatment of atherosclerosis.
Highlights
Cardiovascular diseases (CADs) are the leading causes of death globally
The Di’ao Xinxuekang (DXXK) (160, 80, and 40 mg/kg) and atorvastatin (10 mg/kg) treatment significantly decreased the levels of serum TC, TG, and low-density lipoprotein cholesterol (LDL-C) in high-fat diet-fed Apolipoprotein E (ApoE)−/− mice (P < 0.05 and P < 0.01)
We observed the lipid-lowering and antiatherosclerotic effects of a traditional Chinese herbal medicinal product DXXK in ApoE−/− mice fed a high-fat diet for 18 weeks
Summary
Cardiovascular diseases (CADs) are the leading causes of death globally. Atherosclerosis, characterized by accumulation of macrophage and lipid and protein oxidation products in the intimal layer of arteries, is a fundamental pathological process of CADs (Wang et al, 2017). A number of studies have indicated that both raising HDLC and lowering LDL-C can result in a significant reduction in cardiovascular events due to an increased removal and reduced deposition of body cholesterol (Sirtori and Fumagalli, 2006; Park et al, 2018). The Di’ao Xinxuekang (DXXK) capsule, a traditional Chinese medicinal product extracted from the rhizome of Dioscorea nipponica Makino, has been used in the prevention and treatment of atherosclerotic CAD and other associated diseases for nearly 30 years in China (Yu et al, 2014). Several clinical reports have shown that DXXK can decrease the levels of total cholesterol, triglyceride (TG), and LDL-C and increase the serum HDL-C level as well as the APOA1/APOB ratio in patients with hyperlipidemia, which may be responsible for the effect of DXXK in alleviating atherosclerosis development (Zhou, 1997; Ji, 2001). The mechanism by which DXXK reduces the serum LDL-C level remains unclear
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