Grain polyphenols play an important role in the prevention and treatment of atherosclerosis. Phenolic components such as phenolic acids, anthocyanins and proanthocyanidins in various types of rice can effectively prevent cardiovascular diseases, type II diabetes and other chronic diseases[1]. The 3-deoxyanthocyanins, which are unique in sorghum, have the potential to block atherosclerosis by constraining the oxidation of LDL by antioxidation[2]. Black rice anthocyanins exert anti-atherosclerotic effects by inhibiting macrophage inflammation, reducing thrombocytosis and hypertriglyceridemia[3, 4]. Setaria italica is an annual gramineous plant. The effects of polyphenols on anti-inflammatory, lipid-lowering and antioxidant properties have been reported[5, 6]. Millet shell is a by-product of millet fine processing, and its nutritional value is often neglected. Studies have shown that whole grain consumption with shell is strongly associated with a lower risk of cardiovascular disease[7]. Further studies showed that polyphenols in shell were abundant, and often far more than those in fine grinding grain[8], [9], [10]. Therefore, the effects of millet shell polyphenols in preventing atherosclerosis were discussed.

Cardiovascular disease is recognized as the world's leading killer, and its fatality rate accounts for about half of the annual non-communicable disease deaths[11]. atherosclerosis is the main cause of cardiovascular disease[12]. In the early stage of atherosclerosis, vascular endothelial cells are visibly damaged due to various factors, and low-density lipoprotein (LDL) particles accumulate in the subintima and oxidation to form oxidized low-density lipoprotein (ox-LDL)[13]. At the same time, the damaged intima will attract blood monocytes into the subintima and differentiate into mature macrophages[14]. Mature macrophages phagocytose modified LDL to form macrophage-derived foam cells[15]. The phagocytosis of ox-LDL by macrophages promotes the development of inflammation, and these inflammatory factors and other chemokines stimulate the transition of smooth muscle cells in vascular media from stable contractile type to dedifferentiated synthetic type[16]. Further, synthetic vascular smooth muscle cells migrate into subintima to proliferate and phagocytose lipids to form vascular smooth muscle cell-derived foam cells[17, 18]. Continuous aggregation of two types foam cells gradually forms the core of necrotic and lipid-rich atherosclerotic plaques[19, 20].

Numerous experimental and clinical studies have shown that atherosclerosis is a lipid-driven inflammatory disease of the arterial intima, and the balance between the progression and resolution of inflammation determines the final clinical outcome[21, 22]. The hallmark of chronic inflammation in atherosclerosis is the progressive accumulation of lipids and inflammation, mainly involving monocyte-derived macrophages[23, 24]. The phagocytosis of lipids by macrophages promotes the secretion of inflammatory factors, which further stimulate the proliferation of macrophages to form foam cells. The cycle of lipid accumulation and worsening inflammation stimulates the formation of atherosclerotic plaques[25]. The balance between pro-inflammatory and anti-inflammatory processes controls the direction of lipid-driven inflammation in atherosclerotic lesions. If the balance between pro-inflammatory and anti-inflammatory mediators tends to be inflammatory suppression, it favors dead cells and cholesterol efflux to aid in further inflammation resolution, thereby promoting the formation of stable plaques with small lipid necrotic cores[22].

In this study, millet shell polyphenols (MSPs) suppressed the formation of macrophage-derived foam cells by impeding lipid phagocytosis and inflammatory development of macrophages. Meanwhile, MSPs reduced the generation of smooth muscle cell-derived foam cells by regulating the phenotypic transformation of HASMCs. The reduction of two kinds of foam cells effectively leads to the improvement of atherosclerosis.