Formononetin attenuates atherosclerosis via regulating interaction between KLF4 and SRA in apoE-/- mice
Formononetin attenuates atherosclerosis via regulating interaction between KLF4 and SRA in apoE-/- mice
复制标题
芒柄花素通过调节 apoE(-/-) 小鼠中 KLF4 和 SRA 之间的相互作用来减轻动脉粥样硬化
DOI：
10.7150/thno.38115
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Fan, Guanwei
中科院分区：
文献类型：
--
作者：
Ma, Chuanrui;Xia, Ronglin;Fan, Guanwei
背景和目的：动脉粥样硬化是冠心病的潜在原因。泡沫细胞是动脉粥样硬化的标志，主要来源于单核细胞分化的巨噬细胞和血管平滑肌细胞（VSMCs），通过无限制地吞噬氧化低密度脂蛋白（oxLDL）而形成。因此，抑制单核细胞与内皮细胞的粘附和oxLDL的摄取可能是延缓动脉粥样硬化的突破口。芒柄花素是从黄芪中提取的一种黄酮类化合物，在不同的动物模型中对致动脉粥样硬化因素如肥胖、血脂异常和炎症表现出多种抑制作用。然而，其对动脉粥样硬化的影响仍然未知。在这项研究中，我们确定芒柄花素是否可以抑制动脉粥样硬化，并阐明了潜在的分子mechanism.Methods：ApoE基因缺陷小鼠进行了治疗芒柄花素在高脂饮食16周。治疗后，收集小鼠主动脉、巨噬细胞和血清样品，以确定病变、免疫细胞谱、脂质谱和相关分子的表达。同时，我们研究了芒柄花素对单核细胞粘附，泡沫细胞形成，内皮细胞活化和巨噬细胞极化的影响，在体外和体内。芒柄花素通过改变斑块的组成来增强病变的稳定性。VSMC和巨噬细胞源性泡沫细胞的形成和其在动脉壁中的积聚被芒柄花素减弱，这可能归因于减少SRA表达和减少单核细胞粘附。芒柄花素抑制致动脉粥样硬化单核细胞粘附和炎症。结论：芒柄花素通过调节KLF4与SRA的相互作用，抑制动脉粥样硬化的发生发展，有望成为一种新的抗动脉粥样硬化的药物。
Background and Purpose: Atherosclerosis is an underlying cause of coronary heart disease. Foam cell, a hallmark of atherosclerosis, is prominently derived from monocyte-differentiated macrophage, and vascular smooth muscle cells (VSMCs) through unlimitedly phagocytizing oxidized low-density lipoprotein (oxLDL). Therefore, the inhibition of monocyte adhesion to endothelium and uptake of oxLDL might be a breakthrough point for retarding atherosclerosis. Formononetin, an isoflavone extracted from Astragalus membranaceus, has exhibited multiple inhibitory effects on proatherogenic factors, such as obesity, dyslipidemia, and inflammation in different animal models. However, its effect on atherosclerosis remains unknown. In this study, we determined if formononetin can inhibit atherosclerosis and elucidated the underlying molecular mechanisms.Methods: ApoE deficient mice were treated with formononetin contained in high-fat diet for 16 weeks. After treatment, mouse aorta, macrophage and serum samples were collected to determine lesions, immune cell profile, lipid profile and expression of related molecules. Concurrently, we investigated the effect of formononetin on monocyte adhesion, foam cell formation, endothelial activation, and macrophage polarization in vitro and in vivo.Results: Formononetin reduced en face and aortic root sinus lesions size. Formononetin enhanced lesion stability by changing the composition of plaque. VSMC- and macrophage-derived foam cell formation and its accumulation in arterial wall were attenuated by formononetin, which might be attributed to decreased SRA expression and reduced monocyte adhesion. Formononetin inhibited atherogenic monocyte adhesion and inflammation. KLF4 negatively regulated the expression of SRA at transcriptional and translational level.Conclusions: Our study demonstrate that formononetin can substantially attenuate the development of atherosclerosis via regulation of interplay between KLF4 and SRA, which suggests the formononetin might be a novel therapeutic approach for inhibition of atherosclerosis.