Acetylshikonin attenuates angiotensin II-induced proliferation and motility of human brain smooth muscle cells by inhibiting Wnt/β-catenin signaling
- 96 Downloads
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.
KeywordsCerebrovascular smooth muscle cells Proliferation Angiotensin II Acetylshikonin Wnt/β-catenin pathway
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 2.Yu ZL, Wang JN, Wu XH, Xie HJ, Han Y, Guan YT, Qin Y, Jiang JM. Tanshinone IIA prevents rat basilar artery smooth muscle cells proliferation by inactivation of PDK1 during the development of hypertension. J Cardiovasc Pharmacol Ther. 2015;20(6):563–71. https://doi.org/10.1177/1074248415574743.CrossRefPubMedGoogle Scholar
- 3.Mancia G, Messerli F, Bakris G, Zhou Q, Champion A, Pepine CJ. Blood pressure control and improved cardiovascular outcomes in the International Verapamil SR-Trandolapril Study. Hypertension. 2007;50(2):299–305. https://doi.org/10.1161/HYPERTENSIONAHA.107.090290.CrossRefPubMedGoogle Scholar
- 4.Bihl JC, Zhang C, Zhao Y, Xiao X, Ma X, Chen Y, Chen S, Zhao B, Chen Y. Angiotensin-(1-7) counteracts the effects of Ang II on vascular smooth muscle cells, vascular remodeling and hemorrhagic stroke: role of the NFsmall ka, CyrillicB inflammatory pathway. Vascul Pharmacol. 2015;73:115–23. https://doi.org/10.1016/j.vph.2015.08.007.CrossRefPubMedPubMedCentralGoogle Scholar
- 7.Wang Y, Ma TT, Gao NN, Zhou XL, Jiang H, Guo R, Jia LN, Chang H, Gao Y, Gao ZM, Pan L. Effect of Tongxinluo on pulmonary hypertension and pulmonary vascular remodeling in rats exposed to a low pressure hypoxic environment. J Ethnopharmacol. 2016;194:668–73. https://doi.org/10.1016/j.jep.2016.10.004.CrossRefPubMedGoogle Scholar
- 8.Tsai FJ, Ho TJ, Cheng CF, Liu X, Tsang H, Lin TH, Liao CC, Huang SM, Li JP, Lin CW, Lin JG, Lin JC, Lin CC, Liang WM, Lin YJ. Effect of Chinese herbal medicine on stroke patients with type 2 diabetes. J Ethnopharmacol. 2017;200:31–44. https://doi.org/10.1016/j.jep.2017.02.024.CrossRefPubMedGoogle Scholar
- 10.Li Q, Zeng J, Su M, He Y, Zhu B. Acetylshikonin from Zicao attenuates cognitive impairment and hippocampus senescence in d-galactose-induced aging mouse model via upregulating the expression of SIRT1. Brain Res Bull. 2018;137:311–8. https://doi.org/10.1016/j.brainresbull.2018.01.007.CrossRefPubMedGoogle Scholar
- 28.Chiron D, Martin P, Di Liberto M, Huang X, Ely S, Lannutti BJ, Leonard JP, Mason CE, Chen-Kiang S. Induction of prolonged early G1 arrest by CDK4/CDK6 inhibition reprograms lymphoma cells for durable PI3Kdelta inhibition through PIK3IP1. Cell Cycle. 2013;12(12):1892–900. https://doi.org/10.4161/cc.24928.CrossRefPubMedPubMedCentralGoogle Scholar