Abstract
Atherosclerosis is a major pathogenic driver of cardiovascular diseases. Foam cell formation plays a key role in atherogenesis, which is affected by lipid disorder and inflammation. Therefore, inhibition of foam cell formation is a therapeutic approach for atherosclerosis treatment. Total flavone of Astragalus membranaceus (TFA) is extracted from A. membranaceus that has protective effect on cardiovascular disease. However, the effect of TFA on atherosclerosis and the underlying mechanism remains unknown. In this study, we determined whether TFA could inhibit atherosclerosis and uncovered the underlying mechanism. In vivo, ApoE deficient mice were treated with TFA and high-fat diet for 16 weeks. Subsequently, atherosclerotic lesions, hepatic steatosis and associated genes expression in vitro and in vivo were determined. We found that TFA reduced atherosclerotic lesion size and enhanced plaque stability, which might be attributed to improved lipid disorder, reduced inflammation and decreased monocyte adhesion. Mechanistically, TFA inhibited hepatic steatosis via regulating the genes responsible for lipid metabolism, by which ameliorating the lipid disorder. Moreover, in macrophage, TFA reduced the expression of scavenger receptors such as CD36 and SRA; and promoted the expression of ATP-binding cassette transporter A1 and G1 (ABCA1/G1). More importantly, TFA reduced miR-33 expression and dampened NFκB activity, by which de-repressing ABCA1/G1 activity and inhibiting the inflammation. Collectively, TFA can attenuate atherosclerosis via dual suppression of miR-33 and NFκB pathway, and partially through inhibition of scavenger receptors in macrophage. In addition, TFA ameliorates the hepatic steatosis and lipid disorder, which in turn contributes to the amelioration of atherosclerosis, suggesting that TFA might be a novel therapeutic approach for inhibition of atherosclerosis and hepatic steatosis.
Highlights
Atherosclerosis is the principal risk factor of cardiovascular diseases, which is mainly driven by lipid disorder and inflammation
High cholesterol uptake and low efflux in macrophage can lead to cellular lipid accumulation and the following foam cell formation (Yu et al, 2013), which is mainly determined by the transporters responsible for cholesterol efflux, such as ABCA1 and ABCG1 (Tall et al, 2008); and scavenger receptors in charge of cholesterol uptake, such as, SRA and CD36 (Crucet et al, 2013; de Winther et al, 2000; Nakata et al, 1999)
Mouse anti-intercellular adhesion molecule 1 (ICAM-1)(Cat#: sc107), vascular cell adhesion molecule 1 (VCAM-1)(Cat#: sc13160), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (Cat#: sc365062) SRA (Cat#: sc56777), αSMA (Cat#: sc130617), CD36 (Cat#: sc70644), and CD68 (Cat#: sc20060) monoclonal antibodies were purchased from Santa Cruz Biotechnology, Inc (Santa Cruz, CA)
Summary
Atherosclerosis is the principal risk factor of cardiovascular diseases, which is mainly driven by lipid disorder and inflammation. High cholesterol uptake and low efflux in macrophage can lead to cellular lipid accumulation and the following foam cell formation (Yu et al, 2013), which is mainly determined by the transporters responsible for cholesterol efflux, such as ABCA1 and ABCG1 (Tall et al, 2008); and scavenger receptors in charge of cholesterol uptake, such as, SRA and CD36 (Crucet et al, 2013; de Winther et al, 2000; Nakata et al, 1999). ABCA1/G1-mediated cholesterol efflux is the initial step of reverse cholesterol transport (RCT), by which cholesterol moves out of foam cells in atherosclerotic plaques into liver and into the feces
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