Abstract
Atherosclerosis-related cardiovascular disease is still the predominant cause of death worldwide. Araloside C (AsC), a natural saponin, exerts extensive anti-inflammatory properties. In this study, we explored the protective effects and mechanism of AsC on macrophage polarization in atherosclerosis in vivo and in vitro. Using a high-fat diet (HFD)-fed ApoE-/- mouse model and RAW264.7 macrophages exposed to ox-LDL, AsC was evaluated for its effects on polarization and autophagy. AsC significantly reduced the plaque area in atherosclerotic mice and lipid accumulation in ox-LDL-treated macrophages, promoted M2 phenotype macrophage polarization, increased the number of autophagosomes and modulated the expression of autophagy-related proteins. Moreover, the autophagy inhibitor 3-methyladenine and BECN1 siRNA obviously abolished the antiatherosclerotic and M2 macrophage polarization effects of AsC. Mechanistically, AsC targeted Sirt1and increased its expression, and this increase in expression was associated with increased autophagy and M2 phenotype polarization. In contrast, the effects of AsC were markedly blocked by EX527 and Sirt1 siRNA. Altogether, AsC attenuates foam cell formation and lessens atherosclerosis by modulating macrophage polarization via Sirt1-mediated autophagy.
Highlights
Cardiovascular disease (CVD) is still the leading cause of death worldwide due to its high morbidity and mortality; it reduces human life span and places a heavy burden to the national health care system according to the latest authoritative statistics [1].Atherosclerosis, a major inducer of CVD, is a chronic inflammatory disease arising from an imbalance in lipid metabolism and a maladaptive immune response driven by the accumulation of cholesterol-laden macrophages in the arterial wall [2]
Using a high-fat diet (HFD)-fed ApoE-/- mouse model and RAW264.7 macrophages exposed to Oxidized low-density lipoprotein (ox-LDL), Araloside C (AsC) was evaluated for its effects on polarization and autophagy
To test whether AsC exerts an antiatherosclerotic effect, we first measured the weight, blood lipid levels and atherosclerotic area at the aortic root of high-fat diet (HFD)-treated ApoE-/- mice according to our previous method [24]
Summary
Cardiovascular disease (CVD) is still the leading cause of death worldwide due to its high morbidity and mortality; it reduces human life span and places a heavy burden to the national health care system according to the latest authoritative statistics [1]. Oxidized low-density lipoprotein (ox-LDL), which contributes directly to macrophage polarization, induces foam cell formation, promoting plaque formation [5]. Silent information regulator 1 (Sirt1), a member of the sirtuin class of proteins, is widely studied and shows atheroprotective effects in macrophages [12], endothelial cells [13], and vascular smooth muscle cells [14]. According to the emerging reports of the cardioprotective effects of AsC and the endothelial protective effects of TASAES, we believe that the antiatherosclerotic effects of AsC and its possible molecular mechanism need to be elucidated. Based on our previous research, this study is the first to investigate the antiatherosclerotic effects and underlying mechanism of AsC on ox-LDL-induced foam cell formation. We speculate that AsC attenuates foam cell formation and lessens atherosclerosis by modulating macrophage polarization via Sirt1-mediated autophagy
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