Chronic Diseases Research Center, School of Medicine, Dalian University, Dalian, 116600, China; Department of Physiology and Pathophysiology, School of Medicine, Yanbian University, Yanji, 133002, China.
Department of Physiology and Pathophysiology, School of Medicine, Yanbian University, Yanji, 133002, China.
Chem Biol Interact. 2021 Apr 25;339:109430. doi: 10.1016/j.cbi.2021.109430. Epub 2021 Mar 4.
Connexin-40 (Cx40) and Cx43 are the principal components of gap junctions. Dysregulation of connexin expression is clinically related to cardiac pathologies. 25-Hydroxy protopanaxadiol [25-OH-PPD, 20 (R)-dammarane-3β, 12β, 20, 25-tetrol], known as AD2, is a novel protopanaxadiol extracted from Panax ginseng that exhibits many pharmacological activities, but its effects on cardiac gap junctions are poorly understood. The aim of this study was to evaluate the effects of AD2 on angiotensin II (Ang II)-induced Cx40 and Cx43 dysregulation. In this study, isolated beating rat atria were perfused with Ang II (5 μM) for 1 h to induce Cx40 and Cx43 dysregulation. The effects of AD2 (1.6, 16, and 160 μg/100 g body weight) on Ang II-induced hemodynamics in rats were analyzed by biological recorder, and changes in proteins levels were analyzed by western blotting. The results showed that AD2 ameliorated Ang II-induced hyper hemodynamics and abnormal P-waves, and prevented fibrotic collagen deposition (3.77% ± 1.64%-26.31% ± 1.64% with Ang II, 5.76% ± 0.94% with AD2). Ang II upregulated expression of nuclear factor kappa B, activator protein 1, and transforming growth factor β1, and downregulated of Cx40 and Cx43 expression, which were inhibited by AD2 concomitantly with increased of AMP-activated protein kinase (AMPK) expression via liver kinase B1 activation. The present findings suggest that AD2 inhibited Ang II-induced dysregulation of Cx40 and Cx43 via activation of AMPK signaling, thus highlighting the promise and utility of AD2 for treatment of connexin dysregulation-related heart disease.
间隙连接蛋白 40（Cx40）和 Cx43 是间隙连接的主要成分。连接蛋白表达失调与心脏病理学密切相关。25-羟基原人参二醇[25-OH-PPD，20（R）-达玛烷-3β，12β，20，25-四醇]，又称 AD2，是一种从人参中提取的新型原人参二醇，具有多种药理活性，但对心脏间隙连接的影响知之甚少。本研究旨在评估 AD2 对血管紧张素 II（Ang II）诱导的 Cx40 和 Cx43 失调的影响。在这项研究中，用 Ang II（5 μM）灌流分离的跳动大鼠心房 1 小时，以诱导 Cx40 和 Cx43 失调。用生物记录器分析 AD2（1.6、16 和 160 μg/100 g 体重）对 Ang II 诱导的大鼠血液动力学的影响，并用 Western blot 分析蛋白水平的变化。结果表明，AD2 改善了 Ang II 诱导的高血液动力学和异常 P 波，并防止了纤维胶原沉积（Ang II 为 3.77%±1.64%-26.31%±1.64%，AD2 为 5.76%±0.94%）。Ang II 上调了核因子 kappa B、激活蛋白 1 和转化生长因子 β1 的表达，下调了 Cx40 和 Cx43 的表达，同时通过肝激酶 B1 激活增加 AMP 激活蛋白激酶（AMPK）的表达，抑制了 AD2 的表达。这些发现表明，AD2 通过激活 AMPK 信号通路抑制 Ang II 诱导的 Cx40 和 Cx43 失调，因此突出了 AD2 在治疗连接蛋白失调相关心脏病方面的潜力和应用。
