Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; State Key Laboratory of Component-Based Chinese Medicine, Ministry of Education, Tianjin, 301617, China.
J Ethnopharmacol. 2023 Aug 10;312:116432. doi: 10.1016/j.jep.2023.116432. Epub 2023 Mar 30.
Traditional Chinese drugs, including Buyang Huanwu decoction (BYHWD), have been used in traditional practice to manage cardiovascular and cerebrovascular diseases. However, the effect and mechanisms by which this decoction alleviates diabetes-accelerated atherosclerosis are unknown and require exploration.
This study aims to investigate the pharmacological effects of BYHWD on preventing diabetes-accelerated atherosclerosis, and elucidate its underlying mechanism.
Streptozotocin (STZ)-induced diabetic ApoE mice were treated with BYHWD. Atherosclerotic aortic lesions, endothelial function, mitochondrial morphology, and mitochondrial dynamics-related proteins were evaluated in isolated aortas. High glucose-exposed human umbilical endothelial cells (HUVECs) were treated with BYHWD and its components. AMPK siRNA transfection, Drp1 molecular docking, Drp1 enzyme activity measurement, and so on were used to explore and verify the mechanism.
BYHWD treatment inhibited the worsening of diabetes-accelerated atherosclerosis by lessening atherosclerotic lesions in diabetic ApoE mice, by impeding endothelial dysfunction under diabetic conditions, and by inhibiting mitochondrial fragmentation by lowering protein expression levels of Drp1 and mitochondrial fission-1 protein (Fis1) in diabetic aortic endothelium. In high glucose-exposed HUVECs, BYHWD treatment also downgraded reactive oxygen species, promoted nitric oxide levels, and abated mitochondrial fission by reducing protein expression levels of Drp1 and fis1, but not mitofusin-1 and optic atrophy-1. Interestingly, we found that BYHWD's protective effect against mitochondrial fission is mediated by AMPK activation-dependent reduction of Drp1 levels. The main serum chemical components of BYHWD, ferulic acid, and calycosin-7-glucoside, can reduce the expression of Drp1 by regulating AMPK, and can inhibit the activity of GTPase of Drp1.
The above findings support the conclusion that BYHWD suppresses diabetes-accelerated atherosclerosis by reducing mitochondrial fission through modulation of the AMPK/Drp1 pathway.
包括补阳还五汤（BYHWD）在内的传统中药已在传统实践中用于治疗心脑血管疾病。然而，该方剂缓解糖尿病加速动脉粥样硬化的作用和机制尚不清楚，需要进一步探索。
本研究旨在探讨 BYHWD 预防糖尿病加速动脉粥样硬化的药理作用，并阐明其潜在机制。
采用链脲佐菌素（STZ）诱导糖尿病 ApoE 小鼠给予 BYHWD 治疗。评估分离主动脉中的动脉粥样硬化主动脉病变、内皮功能、线粒体形态和线粒体动力学相关蛋白。用 BYHWD 及其成分处理高糖暴露的人脐静脉内皮细胞（HUVEC）。采用 AMPK siRNA 转染、Drp1 分子对接、Drp1 酶活性测定等方法探讨和验证机制。
BYHWD 治疗抑制了糖尿病 ApoE 小鼠加速动脉粥样硬化的恶化，减轻了糖尿病状态下的内皮功能障碍，并通过降低糖尿病主动脉内皮细胞中 Drp1 和线粒体分裂-1 蛋白（Fis1）的蛋白表达水平来抑制线粒体片段化。在高糖暴露的 HUVEC 中，BYHWD 治疗还通过降低 Drp1 和 fis1 的蛋白表达水平，减轻活性氧、促进一氧化氮水平和抑制线粒体分裂。有趣的是，我们发现 BYHWD 对线粒体分裂的保护作用是通过 AMPK 激活依赖性降低 Drp1 水平介导的。BYHWD 的主要血清化学成分，阿魏酸和毛蕊异黄酮-7-O-葡萄糖苷，可以通过调节 AMPK 降低 Drp1 的表达，并可以抑制 Drp1 的 GTPase 活性。
上述研究结果支持以下结论：BYHWD 通过调节 AMPK/Drp1 通路减少线粒体分裂来抑制糖尿病加速动脉粥样硬化。
