Effect Of Taurours Deoxycholic Acid On In-Stent Restenosis By Regulating Endoplasmic Reticulum Stress

Objective:At present,the role of endoplasmic reticulum(ER)stress in cardiovascular disease has been gradually recognized,tauroursodeoxycholic acid(TUDCA)has been shown to have cardiovascular protective effects by decreasing ER stress.This study aimed to access that TUDCA decreases ER stress,inhibits the dedifferentiation of VSMCs and neointimal proliferation rate,and ultimately reduce in-stent restenosis.Methods and Results:The effect of TUDCA on dedifferentiation of VSMC and ER stress was investigated using wound healing assays,MTT and western blotting in vitro.It was found that the treatment of TUDCA(10-1000?mol/L)significantly inhibited PDGF-BB-induced proliferation and migration in VSMCs in a concentration dependent manner,and decreases the ER stress marker(IRE1,XBP1,KLF4 and GRP78).A total of 18 rabbits were fed an atherogenic diet and balloon injury was used to induce atheroma formation.BMS,BMS+TUDCA and Firebird stents were randomly implanted in the left common carotid artery.Animals were euthanized at 28 days for scanning electron microscope(SEM),histological examination(HE)and immunohistochemistry.We confirmed that there was no significant difference in neointimal coverage on three stents surfaces,but neointimal was significantly less with BMS+TUDCA(1.6±0.2mm2),compared with Firebird(1.90±0.1mm2)and BMS(2.3±0.1mm2),and the percentage of stenosis was lowest with BMS+TUDCA,followed by Firebird,and was significantly higher with BMS(BMS+TUDCA 28±4%,Firebird 35±7%,BMS 40±1%;P<0.001).Furthermore,TUDCA treatment decreased ER stress in BMS+TUDCA group comparing with BMS group.Conclusions:TUDCA inhibits the dedifferentiation of VSMCs by decreasing ER stress,and reduces neointimal proliferation rate and in-stent restenosis,this mechanism is through downregulating the IRE1/XBP1 signaling pathway.