Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Institute of Cardiology, Chongqing Key Laboratory of Hypertension Research, Chongqing, PR China.
Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Institute of Cardiology, Chongqing Key Laboratory of Hypertension Research, Chongqing, PR China; Department of Cardiology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, PR China.
Life Sci. 2019 Mar 15;221:72-82. doi: 10.1016/j.lfs.2019.02.015. Epub 2019 Feb 7.
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.
血管平滑肌细胞（VSMC）的增殖是糖尿病患者血管成形术后内膜增生的病理基础。位于线粒体外膜的转位蛋白（TSPO）已被发现可调节细胞功能障碍中的氧化还原中间产物。我们假设 TSPO 可能调节 VSMC 的增殖和迁移，并参与糖尿病血管成形术后的内膜增生。
通过细胞计数和 MTT 测定法测量细胞增殖。通过 Transwell®和划痕实验测量细胞迁移。通过免疫印迹和免疫荧光染色检测大鼠动脉和高糖处理的 A10 细胞中的 TSPO 表达。通过球囊损伤诱导 2 型糖尿病大鼠颈动脉的新生内膜形成。
糖尿病大鼠和高糖处理的 A10 细胞中的 TSPO 表达增加。siRNA 下调 TSPO 表达可降低高糖诱导的 A10 细胞中 VSMC 的增殖和迁移。这种现象可以通过使用 TSPO 配体 PK 11195 和 Ro5-4864 来模拟。cGMP/PKG 信号参与了 TSPO 配体的作用，因为在 cGMP 或 PKG 抑制剂 ODQ 或 KT5823 存在的情况下，PK 11195 对 VSMC 增殖的作用被阻断。此外，PK 11195 通过抑制 VSMC 增殖显著抑制新生内膜形成。
本研究表明，TSPO 抑制可抑制高血糖诱导的 VSMC 增殖和迁移，从而防止糖尿病患者血管成形术后的动脉粥样硬化和再狭窄。TSPO 可能是减少糖尿病血管成形术后动脉重塑的潜在治疗靶点。
