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Inhibition of angiotensin II-induced cerebrovascular smooth muscle cell proliferation by LRRC8A downregulation through suppressing PI3K/AKT activation

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Abstract

Cerebrovascular smooth muscle cell proliferation is the major contributor to cerebrovascular remodeling and stroke. Chloride channels have been suggested to play an important role in the regulation of smooth muscle cell proliferation. This study aims to investigate the effect of leucine-rich repeat-containing 8A (LRRC8A), an essential component of volume-sensitive chloride channels, on cerebrovascular smooth muscle cell proliferation. The data showed that LRRC8A expression was increased in mouse brain artery during angiotensin II (AngII)-induced cerebrovascular remodeling. Similarly, AngII also increased the expression of LRRC8A in human brain vascular smooth muscle cells (HBVSMCs). Knockdown of LRRC8A by siRNA significantly inhibited AngII-induced the proliferation, migration, and invasion in HBVSMCs. The inhibition of HBVSMCs proliferation by LRRC8A downregulation appeared to be involved in suppression of cell-cycle transition. AngII-induced the decrease in p21 and p27 expression and the increase in CDK4 and cyclin D1 expression were attenuated by LRRC8A downregulation. Moreover, inhibition of LRRC8A suppressed AngII-induced PI3K/AKT activation and reactive oxygen species generation, but had no effect on JNK, ERK, and p38 phosphorylation. In addition, activation of PI3K/AKT-signaling pathways with specific agonists significantly abolished the effect of LRRC8A deficiency on HBVSMC proliferation. This present study demonstrates that knockdown of LRRC8A ameliorates AngII-induced cerebrovascular smooth muscle cell proliferation via inhibiting PI3K/AKT pathway, suggesting that LRRC8A may be a novel molecular target in the treatment of vascular remodeling and stroke.

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Authors and Affiliations

  1. Department of Neurology, People’s Hospital of Zhengzhou University, No. 7 Wai-5 Road, Zhengzhou, 450052, Henan, China

    Jingjing Lu & Jiewen Zhang

  2. Department of Urology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, Henan, China

    Feng Xu

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Lu, J., Xu, F. & Zhang, J. Inhibition of angiotensin II-induced cerebrovascular smooth muscle cell proliferation by LRRC8A downregulation through suppressing PI3K/AKT activation. Human Cell 32, 316–325 (2019). https://doi.org/10.1007/s13577-019-00260-6

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