Theranostics 2020; 10(3):1090-1106. doi:10.7150/thno.38115

Research Paper

Formononetin attenuates atherosclerosis via regulating interaction between KLF4 and SRA in apoE-/- mice

Chuanrui Ma1,2,3, Ronglin Xia7, Shu Yang4, Lipei Liu5, Jing Zhang3, Ke Feng5, Yuna Shang5, Jingtian Qu1,2, Lingwei Li1,2, Ning Chen8, Shixin Xu1,2,3, Wenwen Zhang9, Jingyuan Mao1,2, Jihong Han5,6, Yuanli Chen6, Xiaoxiao Yang6, Yajun Duan6, Guanwei Fan1,2,3✉

1. First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China;
2. Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, Tianjin, China;
3. State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China;
4. Department of Endocrinology, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China;
5. College of Life Sciences, Nankai University, Tianjin; China;
6. School of Food and Biological Engineering, Hefei University of Technology, Hefei, China;
7. Tianjin Hospital, Tianjin, China;
8. School of Materials Science and Engineering, Tianjin University, Tianjin, China;
9. Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China

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Citation:
Ma C, Xia R, Yang S, Liu L, Zhang J, Feng K, Shang Y, Qu J, Li L, Chen N, Xu S, Zhang W, Mao J, Han J, Chen Y, Yang X, Duan Y, Fan G. Formononetin attenuates atherosclerosis via regulating interaction between KLF4 and SRA in apoE-/- mice. Theranostics 2020; 10(3):1090-1106. doi:10.7150/thno.38115. Available from http://www.thno.org/v10p1090.htm

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Abstract

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.

Keywords: formononetin, cholesterol uptake, atherosclerosis, inflammation, foam cells, Krüppel-like factor 4, Scavenger receptor A1