A novel mechanism of inhibiting in-stent restenosis with arsenic trioxide drug-eluting stent: Enhancing contractile phenotype of vascular smooth muscle cells via YAP pathway

Yinping Zhao; Guangchao Zang; Tieying Yin; Xiaoyi Ma; Lifeng Zhou; Lingjuan Wu; Richard Daniel; Yunbing Wang; Juhui Qiu; Guixue Wang

doi:10.1016/j.bioactmat.2020.08.018

A novel mechanism of inhibiting in-stent restenosis with arsenic trioxide drug-eluting stent: Enhancing contractile phenotype of vascular smooth muscle cells via YAP pathway

Bioact Mater. 2020 Sep 4;6(2):375-385. doi: 10.1016/j.bioactmat.2020.08.018. eCollection 2021 Feb.

Authors

Yinping Zhao^{1

2}, Guangchao Zang¹, Tieying Yin², Xiaoyi Ma³, Lifeng Zhou³, Lingjuan Wu⁴, Richard Daniel⁴, Yunbing Wang⁵, Juhui Qiu², Guixue Wang²

Affiliations

¹ Laboratory of Tissue and Cell Biology, Lab Teaching & Management Center, Chongqing Medical University, Chongqing, 400016, China.
² Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, 400030, China.
³ Beijing Amsinomed Medical Co., Ltd, Beijing, 100021, China.
⁴ Medical School, Newcastle University, Newcastle Upon Tyne, NE2 4AX, UK.
⁵ National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610065, China.

Abstract

Objective: Arsenic trioxide (ATO or As₂O₃) has beneficial effects on suppressing neointimal hyperplasia and restenosis, but the mechanism is still unclear. The goal of this study is to further understand the mechanism of ATO's inhibitory effect on vascular smooth muscle cells (VSMCs).

Methods and results: Through in vitro cell culture and in vivo stent implanting into the carotid arteries of rabbit, a synthetic-to-contractile phenotypic transition was induced and the proliferation of VSMCs was inhibited by ATO. F-actin filaments were clustered and the elasticity modulus was increased within the phenotypic modulation of VSMCs induced by ATO in vitro. Meanwhile, Yes-associated protein (YAP) nuclear translocation was inhibited by ATO both in vivo and in vitro. It was found that ROCK inhibitor or YAP inactivator could partially mask the phenotype modulation of ATO on VSMCs.

Conclusions: The interaction of YAP with the ROCK pathway through ATO seems to mediate the contractile phenotype of VSMCs. This provides an indication of the clinical therapeutic mechanism for the beneficial bioactive effect of ATO-drug eluting stent (AES) on in-stent restenosis (ISR).

Keywords: Arsenic trioxide (ATO); Bioactive; In-stent restenosis (ISR); Yes-associated protein (YAP).