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Translocator protein 18 kDa ligand alleviates neointimal hyperplasia in the diabetic rat artery injury model via activating PKG

Gong, Zhengfan, Han, Yu, Wu, Lianpan, Xia, Tianyang, Ren, Hongmei, Yang, Donghai, Gu, Daqian, Wang, He, Hu, Cuimei, He, Duofen, Zhou, Lin, Zeng, Chunyu
Life sciences 2019 v.221 pp. 72-82
animal disease models, atherosclerosis, cGMP-dependent protein kinase, carotid arteries, cell movement, cyclic GMP, fluorescent antibody technique, gene expression regulation, glucose, hyperglycemia, hyperplasia, immunoblotting, ligands, mitochondrial membrane, noninsulin-dependent diabetes mellitus, patients, rats, small interfering RNA, staining, therapeutics
The proliferation of VSMCs is the pathologic basis for intimal hyperplasia after angioplasty in diabetic patients. Translocator protein (TSPO), located in the outer mitochondrial membrane, has been found to regulate redox intermediate components in cell dysfunction. We hypothesized that TSPO may regulate VSMC proliferation and migration, and be involved in the intimal hyperplasia after angioplasty in diabetes.Cell proliferation was measured by cell counting and MTT assays. Cell migration was measured by Transwell® and scratch-wound assays. TSPO expression in arteries of rats and high glucose-treated A10 cells were detected by immunoblotting and immunofluorescence staining. Neointimal formation of carotid artery was induced by balloon injury in type 2 diabetic rat.TSPO expression was increased in the arterial samples from diabetic rats and A10 cells treated with high glucose. Down-regulation of TSPO expression by siRNA decreased the high-glucose-induced VSMC proliferation and migration in A10 cells. This phenomenon could be simulated by using TSPO ligands, PK 11195 and Ro5-4864. cGMP/PKG signals were involved in the TSPO ligand action, since in the presence of cGMP or PKG inhibitor ODQ or KT5823 respectively, the effect of PK 11195 on VSMC proliferation was blocked. Furthermore, PK 11195 significantly inhibited neointimal formation by the inhibition of VSMC proliferation.This study suggests that TSPO inhibition suppresses the proliferation and migration of VSMCs induced by hyperglycemia, consequently, preventing atherosclerosis and restenosis after angioplasty in diabetic conditions. TSPO may be a potential therapeutic target to reduce arterial remodeling induced by angioplasty in diabetes.