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The Role of Tauroursodeoxycholic Acid on Dedifferentiation of Vascular Smooth Muscle Cells by Modulation of Endoplasmic Reticulum Stress and as an Oral Drug Inhibiting In-Stent Restenosis

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Abstract

Purpose

The role of endoplasmic reticulum (ER) stress in cardiovascular disease is now recognized. Tauroursodeoxycholic acid (TUDCA) is known to have cardiovascular protective effects by decreasing ER stress. This study aimed to assess the ability of TUDCA to decrease ER stress, inhibit dedifferentiation of vascular smooth muscle cells (VSMCs), and reduce in-stent restenosis.

Methods

The effect of TUDCA on dedifferentiation of VSMCs and ER stress was investigated in vitro using wound-healing assays, MTT assays, and western blotting. For in vivo studies, 18 rabbits were fed an atherogenic diet to induce atheroma formation. Bare metal stents (BMS), BMS+TUDCA or Firebird stents were implanted in the left common carotid artery. Rabbits were euthanized after 28 days and processed for scanning electron microscope (SEM), histological examination (HE), and immunohistochemistry.

Results

In vitro TUDCA (10–1000 μmol/L) treatment significantly inhibited platelet-derived growth factor (PDGF)-BB-induced proliferation and migration in VSMCs in a concentration-dependent manner and decreased ER stress markers (IRE1, XBP1, KLF4, and GRP78). In vivo, we confirmed no significant difference in neointimal coverage on three stents surfaces; neointimal was significantly lower with BMS+TUDCA (1.6 ± 0.2 mm2) compared with Firebird (1.90 ± 0.1 mm2) and BMS (2.3 ± 0.1 mm2). Percent stenosis was lowest for BMS+TUDCA, then Firebird, and was significantly higher with BMS (28 ± 4%, 35 ± 7%, 40 ± 1%; respectively; P < 0.001). TUDCA treatment decreased ER stress in the BMS+TUDCA group compared with BMS.

Conclusions

TUDCA inhibited dedifferentiation of VSMCs by decreasing ER stress and reduced in-stent restenosis, possibly through downregulation of the IRE1/XBP1 signaling pathway.

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Acknowledgments

The authors thank the Faculty of Agriculture, Life and Environment Science at Zhejiang University for their valuable technical assistance. We thank Sarah Bubeck, Ph.D., from Liwen Bianji, Edanz Editing China (www.liwenbianji.cn/ac), for editing the English text of a draft of this manuscript.

Funding

This study was supported by Co construction of Provincial Department key project (Grant No. WKJ-ZJ-1729) and Zhejiang Science and Technology Department Animal Experimental Research Project (2017C37141).

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Authors and Affiliations

  1. Department of Cardiology, Shaoxing People’s Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), No. 568 Zhongxing North Road, Shaoxing, Zhejiang, China

    Hangqi Luo, Jufang Chi, Hui Lin, Feidan Gao, Tingjuan Ni, Liping Meng, Jie Zhang, Chengjian Jiang, Zheng Ji, Haitao Lv & Hangyuan Guo

  2. Zhejiang University School of Medicine, Zhejiang, Hangzhou, China

    Hangqi Luo

  3. Department of Cardiology, Wenzhou City Hospital of Traditional Chinese Medicine and Western Medicine Combined, Wenzhou, Zhejiang, China

    Changzuan Zhou

  4. Department of Cardiology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China

    Sunlei Pan

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  1. Hangqi Luo
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Correspondence to Hangyuan Guo.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Luo, H., Zhou, C., Chi, J. et al. The Role of Tauroursodeoxycholic Acid on Dedifferentiation of Vascular Smooth Muscle Cells by Modulation of Endoplasmic Reticulum Stress and as an Oral Drug Inhibiting In-Stent Restenosis. Cardiovasc Drugs Ther 33, 25–33 (2019). https://doi.org/10.1007/s10557-018-6844-4

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