Liu Silin, Pan Xianmei, Cheng Wenbin, Deng Bo, He Yu, Zhang Lei, Ning Yile, Li Jing
Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China.
Front Pharmacol. 2020 May 25;11:768. doi: 10.3389/fphar.2020.00768. eCollection 2020.
Piezo1, a mechanosensitive Ca-permeable non-selective cationic ion channel protein, is involved in a wide range of biological processes and plays crucial roles in vascular development. However, the pharmacology of this protein is in its infancy. Yoda1, the first specific chemical activator of Piezo1 channels, can activate Piezo1 in absence of mechanical stimulation. Hence, we sought to identify inhibitors of Yoda1 from Traditional Chinese Medicine (TCM). Intracellular Ca measurements were conducted in human umbilical vein endothelial cells (HUVECs), HEK 293T cells overexpressing TRPC5 and TRPM2 channels, as well as in CHO K1 cells overexpressing TRPV4 channels. We identified tubeimoside I (TBMS1) as a strong inhibitor of the Yoda1 response and demonstrated its selectivity for the Piezo1 channels. Similarly, Yoda1-induced inhibitory results were obtained in Piezo1 wild-type overexpressed cells, murine liver endothelial cells (MLECs), and macrophages. The physiological responses of TBMS1 were identified by isometric tension, which can inhibit Yoda1 relaxation of aortic rings. Our results demonstrated that TBMS1 can effectively antagonize Yoda1 induced Piezo1 channel activation. This study sheds light on the existence of Yoda1 inhibitors and improves the understanding of vascular pharmacology through Piezo1 channels.
Piezo1是一种机械敏感的钙离子通透非选择性阳离子通道蛋白，参与广泛的生物过程，并在血管发育中发挥关键作用。然而，这种蛋白质的药理学研究尚处于起步阶段。Yoda1是Piezo1通道的首个特异性化学激活剂，能够在无机械刺激的情况下激活Piezo1。因此，我们试图从中药中寻找Yoda1的抑制剂。我们在人脐静脉内皮细胞（HUVECs）、过表达TRPC5和TRPM2通道的HEK 293T细胞以及过表达TRPV4通道的CHO K1细胞中进行了细胞内钙离子测量。我们鉴定出土贝母苷甲（TBMS1）是Yoda1反应的强效抑制剂，并证明了其对Piezo1通道的选择性。同样，在过表达Piezo1野生型的细胞、小鼠肝内皮细胞（MLECs）和巨噬细胞中也获得了Yoda1诱导的抑制结果。通过等长张力鉴定了TBMS1的生理反应，其可抑制Yoda1诱导的主动脉环舒张。我们的结果表明，TBMS1能够有效拮抗Yoda1诱导的Piezo1通道激活。这项研究揭示了Yoda1抑制剂的存在，并通过Piezo1通道增进了对血管药理学的理解。
