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Apatinib Through Activating the RhoA/ROCK Signaling Pathway to Cause Dysfunction of Vascular Smooth Muscle Cells

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Abstract

Vascular smooth muscle cells (VSMCs) are associated with differentiated, organized, and contractile phenotype under the effect of various types of physiological conditions those are associated with migratory, proliferative, and synthetic phenotype under the effect of various types of stimuli, which dysfunction drives many cardiovascular diseases. Abnormal cell proliferation and invasion of VSMCs are among the primary causes of hypertension. Apatinib is a small-molecule tyrosine kinase inhibitor (TKI) that highly selectively binds to and strongly inhibits VEGFR-2. Previous studies have confirmed that the TKIs can raise blood pressure through RhoA/ROCK pathway. LARG is a key gene in the RhoA/ROCK pathway and plays a critical role in the continuous vasoconstriction function because it regulates part of signal transduction in VSMCs. In this study, an in vitro experiment was conducted to observe that apatinib caused dysfunction of MOVAS cells through the RhoA/ROCK signalling pathway and Y27632, a nonspecific ROCK inhibitor, and knockout of LARG gene can improve the proliferation, antiapoptosis, oxidative stress, and mitochondrial autophagy of apatinib-induced MOVAS cells. These findings suggest that activation of the RhoA/ROCK signalling pathway could be the underlying mechanism of apatinib-induced dysfunction of MOVAS cells, while ROCK inhibitor and knockout of LARG gene have potential therapeutic value.

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Abbreviations

RhoA:

Rho-associated

ROCK:

Rho-associated coiled-coil domain-containing protein kinase

LARG:

Leukaemia-associated Rho-GEF

BP:

Blood pressure

TKIs:

Tyrosine kinase inhibitors

VEGFR-2:

Vascular endothelial growth factor receptor-2

VSMCs:

Vascular smooth muscle cells

MYPT1:

Myosin phosphatase target-1

MLC:

Myosin light chain

MLCP:

Myosin light chain phosphatase

CCK-8:

Cell counting kit-8

shRNA:

RNA-short hairpin RNA

ET-1:

Endothelin-1

eNOS:

Endothelial nitric oxide synthase

iNOS:

Inducible nitric oxide synthase

a-SMA:

Alpha smooth muscle actin

LC3:

MAP1LC3

ROS:

Photo-activated reactive oxygen species

Bax:

BCL2-Associated X

Bcl2:

B cell lymphoma/leukaemia-2

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Funding

This study was supported by the National Natural Science Foundation of China (NSFC-81960086, NSFC-81670385 to Jing Yu) and Science and Technology Department of Gansu Province (21JR1RA150) and Education Department of Gansu Province (2021B-043), and Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital (2020QN-07).

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Author notes

  1. Wenjuan Wang and Qingjian He contributed equally to this work.

Authors and Affiliations

  1. Department of Hypertension Center, Lanzhou University Second Hospital, Chengguan District, CuiyingmenLanzhou, No. 82, China

    Wenjuan Wang, Chenchen Zhuang, Haodong Zhang, Xin Fan, Qiongying Wang, Miaomiao Qi, Runmin Sun, Caie Li & Jing Yu

  2. Department of Breast and Thyroid Surgery, Zhoushan Hospital of Zhejiang Province, Zhoushan, China

    Qingjian He

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  1. Wenjuan Wang
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  2. Qingjian He
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  3. Chenchen Zhuang
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  5. Xin Fan
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Contributions

Wenjuan Wang performed the experiments. Jing Yu, Qiongying Wang Caie Li, and Wenjuan Wang designed the study, and Wenjuan Wang wrote the initial draft of the manuscript. Qingjian He, Haodong Zhang, Chenchen Zhuang, and Fanxin analysed the data. All the authors have read and approved the final manuscript.

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Correspondence to Jing Yu.

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Wang, W., He, Q., Zhuang, C. et al. Apatinib Through Activating the RhoA/ROCK Signaling Pathway to Cause Dysfunction of Vascular Smooth Muscle Cells. Appl Biochem Biotechnol 194, 5367–5385 (2022). https://doi.org/10.1007/s12010-022-04020-5

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