Department of Traditional Chinese Medicine, Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510260, PR China; School of Chinese medicine, Hong Kong Baptist University (HKBU), Kowloon Tong, Kowloon, Hong Kong, PR China.
Department of Traditional Chinese Medicine, Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510260, PR China.
Phytomedicine. 2024 Oct;133:155885. doi: 10.1016/j.phymed.2024.155885. Epub 2024 Jul 20.
Endothelial dysfunction (ED), characterized by markedly reduced nitric oxide (NO) bioavailability, vasoconstriction, and a shift toward a proinflammatory and prothrombotic state, is an important contributor to hypertension, atherosclerosis, and other cardiovascular diseases. Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is widely involved in cardiovascular development. Przewaquinone A (PA), a lipophilic diterpene quinone extracted from Salvia przewalskii Maxim, inhibits vascular contraction.
Herein, the goal was to explore the protective effect of PA on ED in vivo and in vitro, as well as the underlying mechanisms.
A human umbilical vein endothelial cell (HUVEC) model of ED induced by angiotensin II (AngII) was used for in vitro observations. Levels of AMPK, endothelial nitric oxide synthase (eNOS), vascular cell adhesion molecule-1 (VCAM-1), nitric oxide (NO), and endothelin-1 (ET-1) were detected by western blotting and ELISA. A mouse model of hypertension was established by continuous infusion of AngII (1000 ng/kg/min) for 4 weeks using osmotic pumps. Following PA and/or valsartan administration, NO and ET-1 levels were measured. The levels of AMPK signaling-related proteins in the thoracic aorta were evaluated by immunohistochemistry. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were measured using the tail cuff method. Isolated aortic vascular tone measurements were used to evaluate the vasodilatory function in mice. Molecular docking, molecular dynamics, and surface plasmon resonance imaging (SPRi) were used to confirm AMPK and PA interactions.
PA inhibited AngII-induced vasoconstriction and vascular adhesion as well as activated AMPK signaling in a dose-dependent manner. Moreover, PA markedly suppressed blood pressure, activated vasodilation in mice following AngII stimulation, and promoted the activation of AMPK signaling. Furthermore, molecular simulations and SPRi revealed that PA directly targeted AMPK. AMPK inhibition partly abolished the protective effects of PA against endothelial dysfunction.
PA activates AMPK and ameliorates endothelial dysfunction during hypertension.
内皮功能障碍（ED）的特征是一氧化氮（NO）生物利用度显著降低、血管收缩以及向促炎和促血栓形成状态转变，是高血压、动脉粥样硬化和其他心血管疾病的重要诱因。腺苷 5'-单磷酸（AMP）激活的蛋白激酶（AMPK）广泛参与心血管发育。Przewaquinone A（PA）是从丹参中提取的脂溶性二萜醌，可抑制血管收缩。
本研究旨在探讨 PA 对体内和体外 ED 的保护作用及其潜在机制。
采用血管紧张素 II（AngII）诱导的人脐静脉内皮细胞（HUVEC）ED 模型进行体外观察。通过 Western blot 和 ELISA 检测 AMPK、内皮型一氧化氮合酶（eNOS）、血管细胞黏附分子-1（VCAM-1）、NO 和内皮素-1（ET-1）水平。通过渗透压泵持续输注 AngII（1000ng/kg/min）4 周建立高血压小鼠模型。给予 PA 和/或缬沙坦后，测量 NO 和 ET-1 水平。通过免疫组织化学评估胸主动脉中 AMPK 信号相关蛋白的水平。采用尾套法测量收缩压（SBP）、舒张压（DBP）和平均动脉压（MAP）。采用离体主动脉血管张力测量法评估小鼠的血管舒张功能。通过分子对接、分子动力学和表面等离子体共振成像（SPRi）确认 AMPK 和 PA 的相互作用。
PA 呈剂量依赖性抑制 AngII 诱导的血管收缩和血管黏附，并激活 AMPK 信号。此外，PA 显著降低 AngII 刺激后的小鼠血压，促进血管舒张，并激活 AMPK 信号。进一步的分子模拟和 SPRi 显示 PA 直接靶向 AMPK。AMPK 抑制部分消除了 PA 对内皮功能障碍的保护作用。
PA 通过激活 AMPK 改善高血压期间的内皮功能障碍。
