吡格列酮可抑制高糖诱导的人隐静脉移植物中的氧化应激、基质金属蛋白酶介导的炎症反应及血管功能障碍。

Pioglitazone inhibits oxidative stress, MMP-mediated inflammation and vascular dysfunction in high glucose-induced human saphenous vein grafts.

作者信息

Onursal Ceylan, Reel Buket, Bintepe Caglar, Guzeloglu Mehmet, Ersoy Nevin, Bagriyanik Alper

机构信息

Ege University, Faculty of Pharmacy, Department of Pharmacology, 35100 Bornova-Izmir, Turkey.

Ege University, Faculty of Pharmacy, Department of Clinical Pharmacy, 35100 Bornova-Izmir, Turkey.

出版信息

J Diabetes Complications. 2023 Apr;37(4):108421. doi: 10.1016/j.jdiacomp.2023.108421. Epub 2023 Feb 8.

DOI:10.1016/j.jdiacomp.2023.108421

PMID:36905721

Abstract

AIMS

The aim of this study was to investigate the effects of pioglitazone on reactive oxygen species (ROS), expressions/activities of MMPs and TIMP-2, and VSMC proliferation and vascular reactivity in high glucose (HG)-induced human saphenous vein (HSV) grafts.

METHODS

HSV grafts (n = 10) obtained from patients undergoing CABG were incubated with 30 mM glucose and/or 10 μM pioglitazone or 0.1 % DMSO for 24 h after endothelium removal. ROS levels were examined by chemiluminescence assay, MMP-2,-9,-14, TIMP-2, and α-SMA expression/activity was determined by gelatine zymography/immunohistochemistry. Vascular reactivity to potassium chloride, noradrenaline, serotonin, prostaglandin F and papaverine was assessed in HSVs.

RESULTS

HG induced superoxide anion (SA) (123 %) and other ROS levels (159 %), up-regulated MMP-2 expression (180 %)/activity (79 %), MMP-14 expression (24 %) and MMP-9 activity while down-regulating TIMP-2 expression (27 %). HG elevated total MMP-2/TIMP-2 ratio (483 %) and MMP-14/TIMP-2 ratio (78 %). However, HG plus pioglitazone inhibited SA (30 %) and other ROS levels (29 %), down-regulated MMP-2 expression (76 %)/activity (83 %), MMP-14 expression (38 %) and MMP-9 activity, while reversing TIMP-2 expression (44 %). HG plus pioglitazone decreased total MMP-2/TIMP-2 ratio (91 %) and MMP-14/TIMP-2 ratio (59 %). HG impaired contractions to all agents but pioglitazone improved them.

CONCLUSIONS

Pioglitazone may contribute to the prevention of restenosis and maintaining vascular function in HSV grafts of DM patients undergoing CABG.

摘要

目的

本研究旨在探讨吡格列酮对高糖（HG）诱导的人隐静脉（HSV）移植物中活性氧（ROS）、基质金属蛋白酶（MMPs）和金属蛋白酶组织抑制因子-2（TIMP-2）的表达/活性，以及血管平滑肌细胞（VSMC）增殖和血管反应性的影响。

方法

从接受冠状动脉旁路移植术（CABG）的患者获取HSV移植物（n = 10），去除内皮后，用30 mM葡萄糖和/或10 μM吡格列酮或0.1%二甲基亚砜（DMSO）孵育24小时。通过化学发光法检测ROS水平，用明胶酶谱法/免疫组织化学法测定MMP-2、-9、-14、TIMP-2和α-平滑肌肌动蛋白（α-SMA）的表达/活性。评估HSV对氯化钾、去甲肾上腺素、5-羟色胺、前列腺素F和罂粟碱的血管反应性。

结果

HG诱导超氧阴离子（SA）水平升高（123%）和其他ROS水平升高（159%），上调MMP-2表达（180%）/活性（79%）、MMP-14表达（24%）和MMP-9活性，同时下调TIMP-2表达（27%）。HG使总MMP-2/TIMP-2比值升高（483%）和MMP-14/TIMP-2比值升高（78%）。然而，HG加吡格列酮可抑制SA（30%）和其他ROS水平（29%），下调MMP-2表达（76%）/活性（83%）、MMP-14表达（38%）和MMP-9活性，同时逆转TIMP-2表达（44%）。HG加吡格列酮降低总MMP-2/TIMP-2比值（91%）和MMP-14/TIMP-2比值（59%）。HG损害对所有药物的收缩反应，但吡格列酮可改善这些反应。