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.

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.