First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China.
Br J Pharmacol. 2022 Jan;179(2):252-269. doi: 10.1111/bph.15720. Epub 2021 Dec 2.
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.
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.
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.
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.
动脉粥样硬化是心血管疾病的潜在病因之一。斑块中泡沫细胞和坏死核心的形成是动脉粥样硬化的标志，其由巨噬细胞中的脂质沉积、细胞凋亡和炎症引起。巨噬细胞自噬是一种关键的抗动脉粥样硬化过程，自噬缺陷通过增强泡沫细胞形成、细胞凋亡和炎症加重动脉粥样硬化。因此，增强自噬可能是动脉粥样硬化治疗的一种策略。毛蕊异黄酮是黄芪根中的一种黄酮类化合物，具有抗氧化和抗炎作用，因此有可能降低心血管疾病的风险。然而，毛蕊异黄酮的抗动脉粥样硬化作用及其涉及的机制尚不清楚。在这项研究中，我们评估了毛蕊异黄酮对自噬和动脉粥样硬化的潜在益处，并揭示了其潜在的机制。
在本研究中，apoE 小鼠在高脂肪饮食喂养 16 周的同时给予毛蕊异黄酮和/或自噬抑制剂氯喹，并测定动脉粥样硬化的发展、自噬活性和涉及的机制。
毛蕊异黄酮通过促进自噬来预防动脉粥样硬化和增强斑块稳定性。毛蕊异黄酮通过增强自噬抑制泡沫细胞形成、炎症和细胞凋亡。MLKL 被证明是一种新的自噬调节剂，可以被 KLF2 负调控。机制上，毛蕊异黄酮通过调节 KLF2-MLKL 信号通路来改善自噬，从而抑制动脉粥样硬化的发生。
本研究表明，毛蕊异黄酮的抗动脉粥样硬化作用是通过上调 KLF2-MLKL 介导的自噬来实现的，这不仅为动脉粥样硬化的发病机制提供了新的认识，而且还将毛蕊异黄酮鉴定为一种治疗动脉粥样硬化的潜在药物候选物。
