Zhang Qi-Qiang, Chen Feng-Hua, Wang Fei, Di Xue-Mei, Li Wei, Zhang Hai
Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.
School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China.
Front Pharmacol. 2022 Mar 11;13:841435. doi: 10.3389/fphar.2022.841435. eCollection 2022.
The monoester alkaloids in , including benzoylaconitine (BAC), benzoylmesaconine, and benzoylhypaconitine, were found to have anti-hypertensive effects in spontaneously hypertension rats (SHRs), of which BAC is the strongest. However, its antihypertensive target and underlying molecular mechanisms remain unclear. In this study, first, we screened the antihypertensive targets of BAC by using the CVDPlatform (www.cbligand.org/CVD) and found that ACE/ACE2 are the most possible targets. Then, we verified the effect of BAC on ACE/ACE2 by virtual docking, SPR, enzyme activity assay, and HUVECs cell experiment. We found that BAC could bind with ACE/ACE2, inhibit ACE activity and protein expression, and activate ACE2 enzyme activity. Using vascular function test we found that BAC could target ACE/ACE2 to enhance endothelium-dependent vasorelaxation. In BAC-treated SHRs, the levels of ACE and AngII in serum were reduced while Ang (1-7) was increased significantly, and the expression of ACE was reduced, which suggested that BAC can inhibit ACE and activate ACE2 to inhibit AngI to AngII and promote AngII to Ang (1-7) to inhibit vasoconstriction and finally attenuate hypertension. Furthermore, the signaling pathways with regard to vasorelaxation and vascular inflammation were investigated. The results showed that BAC could significantly activate Akt/eNOS, increase NO production, and promote endothelial-related vasodilation; BAC could also reduce inflammatory factors TNF-α and IL6, inhibition of COX-2 expression, and IKB-α phosphorylation to reduce vascular inflammation in SHRs. In brief, BAC targets ACE/ACE2 to enhance endothelium-dependent vasorelaxation and reduce vascular inflammation to attenuate hypertension as a potential modulator of the renin-angiotensin system.
在[具体药物或物质]中的单酯生物碱，包括苯甲酰乌头碱（BAC）、苯甲酰新乌头碱和苯甲酰次乌头碱，被发现在自发性高血压大鼠（SHR）中具有抗高血压作用，其中BAC的作用最强。然而，其抗高血压靶点和潜在的分子机制仍不清楚。在本研究中，首先，我们通过使用CVDPlatform（www.cbligand.org/CVD）筛选了BAC的抗高血压靶点，发现ACE/ACE2是最可能的靶点。然后，我们通过虚拟对接、表面等离子体共振（SPR）、酶活性测定和人脐静脉内皮细胞（HUVECs）实验验证了BAC对ACE/ACE2的作用。我们发现BAC可以与ACE/ACE2结合，抑制ACE活性和蛋白表达，并激活ACE2酶活性。通过血管功能测试，我们发现BAC可以靶向ACE/ACE2以增强内皮依赖性血管舒张。在BAC处理的SHR中，血清中ACE和血管紧张素II（AngII）的水平降低，而血管紧张素（1-7）显著增加，且ACE的表达降低，这表明BAC可以抑制ACE并激活ACE2，抑制血管紧张素I（AngI）向AngII的转化，并促进AngII向Ang（1-7）的转化，从而抑制血管收缩并最终减轻高血压。此外，还研究了与血管舒张和血管炎症相关的信号通路。结果表明，BAC可以显著激活Akt/内皮型一氧化氮合酶（eNOS）信号通路，增加一氧化氮（NO）的产生，并促进内皮相关的血管舒张；BAC还可以降低炎症因子肿瘤坏死因子-α（TNF-α）和白细胞介素6（IL6）的水平，抑制环氧化酶-2（COX-2）的表达以及IκB-α的磷酸化，从而减轻SHR中的血管炎症。简而言之，作为肾素-血管紧张素系统的潜在调节剂，BAC靶向ACE/ACE2以增强内皮依赖性血管舒张并减少血管炎症，从而减轻高血压。
