Calycosin ameliorates atherosclerosis by enhancing autophagy via regulating the interaction between KLF2 and MLKL in apolipoprotein E gene-deleted mice

Ma, Chuanrui1,2; Wu, Han3,4; Yang, Guangyan3,4; Xiang, Jiaqing3,4; Feng, Ke5; Zhang, Jing1,2; Hua, Yunqing1,2; Kang, Lin3,4,6; Fan, Guanwei1,2; Yang, Shu3,4,7

2021-12-01

10.1111/bph.15720

BRITISH JOURNAL OF PHARMACOLOGY   影响因子和分区

0007-1188

1476-5381

Background and Purpose Atherosclerosis is one of the underlying causes of cardiovascular disease. Formation of foam cells and necrotic core in the plaque is a hallmark of atherosclerosis, which results from lipid deposition, apoptosis, and inflammation in macrophages. Macrophage autophagy is a critical anti-atherogenic process and defective autophagy aggravates atherosclerosis by enhancing foam cell formation, apoptosis, and inflammation. Hence, enhancing autophagy can be a strategy for atherosclerosis treatment. Calycosin, a flavonoid from Radix Astragali, displays anti-oxidant and anti-inflammatory activities and therefore is potential to reduce the risk of cardiovascular disease. However, the anti-atherogenic effect of calycosin and the involved mechanism remains unclear. In this study, we assessed the potential benefits of calycosin on autophagy and atherosclerosis, and revealed the underlying mechanism. Experimental Approach In this study, apoE(-/-) mice were fed high-fat diet for 16 weeks in the presence of calycosin and/or autophagy inhibitor chloroquine, which was followed by determination of atherosclerosis development, autophagy activity, and involved mechanisms. Key Results Calycosin protected against atherosclerosis and enhanced plaque stability via promoting autophagy. Calycosin inhibited foam cell formation, inflammation, and apoptosis by enhancing autophagy. MLKL was demonstrated as a new autophagy regulator, which can be negatively regulated by KLF2. Mechanistically, inhibitory effects of calycosin on atherogenesis were via improved autophagy through KLF2-MLKL signalling pathway modulation. Conclusions and Implications This study demonstrated the atheroprotective effect of calycosin was through upregulating KLF2-MLKL-mediated autophagy, which not only proposed novel mechanistic insights into t atherogenesis but also identified calycosin as a potential drug candidate for atherosclerosis treatment.

atherosclerosis autophagy calycosin KLF2 MLKL

SCI

英语

通讯

Natural Science Foundation of Tianjin["20JCQNJC00260","19JCQNJC12600"] ; Research Project of the Tianjin Education Commission[2019KJ044] ; National Key R&D Program of China[2018YFC1704500] ; National Natural Science Foundation of China[82000824,82003747]

Pharmacology & Pharmacy

Pharmacology & Pharmacy

WOS:000725323300001

WILEY

PHARMACOLOGY & TOXICOLOGY

Web of Science

1.Tianjin Univ Tradit Chinese Med, Teaching Hosp 1, Tianjin, Peoples R China
2.Natl Clin Res Ctr Chinese Med Acupuncture & Moxib, Tianjin, Peoples R China
3.Jinan Univ, Clin Med Coll 2, Shenzhen Peoples Hosp, Dept Endocrinol, Shenzhen 518020, Guangdong, Peoples R China
4.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen 518020, Guangdong, Peoples R China
5.Nankai Univ, Coll Life Sci, Tianjin, Peoples R China
6.Shenzhen Peoples Hosp, Biobank Natl Innovat Ctr Adv Med Devices, Shenzhen, Peoples R China
7.Jinan Univ, Integrated Chinese & Western Med Postdoctoral Res, Guangzhou, Peoples R China

Ma, Chuanrui,Wu, Han,Yang, Guangyan,et al. Calycosin ameliorates atherosclerosis by enhancing autophagy via regulating the interaction between KLF2 and MLKL in apolipoprotein E gene-deleted mice[J]. BRITISH JOURNAL OF PHARMACOLOGY,2021.

Ma, Chuanrui.,Wu, Han.,Yang, Guangyan.,Xiang, Jiaqing.,Feng, Ke.,...&Yang, Shu.(2021).Calycosin ameliorates atherosclerosis by enhancing autophagy via regulating the interaction between KLF2 and MLKL in apolipoprotein E gene-deleted mice.BRITISH JOURNAL OF PHARMACOLOGY.

Ma, Chuanrui,et al."Calycosin ameliorates atherosclerosis by enhancing autophagy via regulating the interaction between KLF2 and MLKL in apolipoprotein E gene-deleted mice".BRITISH JOURNAL OF PHARMACOLOGY (2021).