Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, China.
Department of Pathophysiology, Wenzhou Medical University, University Town, Chashan, Wenzhou, 325035, Zhejiang, China.
Hum Cell. 2018 Jul;31(3):242-250. doi: 10.1007/s13577-018-0207-0. Epub 2018 Apr 23.
Cerebrovascular smooth muscle cell proliferation and migration contribute to hyperplasia in case of cerebrovascular remodeling and stroke. In the present study, we investigated the effects of acetylshikonin, the main ingredient of a Chinese traditional medicine Zicao, on human brain vascular smooth muscle cell (HBVSMCs) proliferation and migration induced by angiotensin II (AngII), and the underlying mechanisms. We found that acetylshikonin treatment significantly inhibited AngII-induced HBVSMCs proliferation and cell cycle transition from G1 to S phase. Wound-healing assay and Transwell assay showed that AngII-induced cell migration and invasion were markedly attenuated by acetylshikonin. In addition, AngII challenge significantly induced Wnt/β-catenin signaling activation, as evidenced by increased β-catenin phosphorylation and nuclear translocation and GSK-3β phosphorylation. However, acetylshikonin treatment inhibited the activation of Wnt/β-catenin signaling. Consequently, western blotting analysis revealed that acetylshikonin effectively reduced the expression of downstream target genes in AngII-treated cells, including c-myc, survivin and cyclin D1, which contributed to the inhibitory effect of acetylshikonin on HBVSMCs proliferation. Further, stimulation with recombinant Wnt3a dramatically reversed acetylshikonin-mediated inhibition of proliferation and cell cycle transition in HBVSMCs. Our study demonstrates that acetylshikonin prevents AngII-induced cerebrovascular smooth muscle cells proliferation and migration through inhibition of Wnt/β-catenin pathway, indicating that acetylshikonin may present a potential option for the treatment of cerebrovascular remodeling.
脑血管平滑肌细胞增殖和迁移导致脑血管重构和中风时的增生。在本研究中，我们研究了乙酰紫草素（中国传统药物紫草的主要成分）对血管紧张素 II（AngII）诱导的人脑血管平滑肌细胞（HBVSMCs）增殖和迁移的影响及其潜在机制。我们发现乙酰紫草素处理可显著抑制 AngII 诱导的 HBVSMCs 增殖和细胞周期从 G1 期向 S 期的转变。划痕愈合实验和 Transwell 实验表明，乙酰紫草素显著减弱 AngII 诱导的细胞迁移和侵袭。此外，AngII 刺激显著诱导 Wnt/β-catenin 信号通路激活，表现为β-catenin 磷酸化和核转位以及 GSK-3β 磷酸化增加。然而，乙酰紫草素处理抑制了 Wnt/β-catenin 信号通路的激活。因此，Western blot 分析显示，乙酰紫草素有效降低了 AngII 处理细胞中下游靶基因的表达，包括 c-myc、survivin 和 cyclin D1，这有助于乙酰紫草素抑制 HBVSMCs 增殖。此外，重组 Wnt3a 的刺激显著逆转了乙酰紫草素介导的 HBVSMCs 增殖和细胞周期转变的抑制作用。我们的研究表明，乙酰紫草素通过抑制 Wnt/β-catenin 通路防止 AngII 诱导的脑血管平滑肌细胞增殖和迁移，表明乙酰紫草素可能是治疗脑血管重构的一种潜在选择。
