Regenerative Medicine Institute, REMEDI, National University of Ireland Galway, Ireland.
Atherosclerosis. 2012 Apr;221(2):325-32. doi: 10.1016/j.atherosclerosis.2012.01.036. Epub 2012 Feb 1.
The most common cause of death in diabetes mellitus is cardiovascular disease. Patients frequently undergo vascular intervention such as stenting. The occurrence of in stent restenosis (ISR) has been reduced by the use of drug eluting stents in non-diabetic patients but the incidence of restenosis and stent thrombosis remains higher in diabetic patients. We investigated the pathogenesis of in stent restenosis in an animal model of type 2 diabetes mellitus.
Stents were placed in Zucker Fatty rat (ZFR) and wild type rat carotid arteries, and tissues were harvested 14 days post surgery for morphometric analysis. Unstented carotid arteries from both groups were harvested for microarray analysis. In vitro apoptosis, proliferation and migration assays were performed on rat and human aortic endothelial cells (EC). ZFRs developed an exaggerated intimal response to stent placement compared to wild type controls 14 days post stent placement. MRP8 and MRP14 were up-regulated in unstented ZFR carotid arteries in comparison to controls. Expression of MRP8/14 was also elevated in EC exposed to high glucose conditions. EC function was impaired by high glucose concentrations, and this effect could be mimicked by MRP8 over-expression. MRP8 knockdown by shRNA significantly restored EC function after exposure to high glucose concentrations. MRP8 expression in glucose exposed cells was also inhibited using pharmacological blockade of glucose-induced pathways.
EC dysfunction caused by elevated glucose levels could be mimicked by MRP8/14 over-expression and reversed/prevented by MRP8 knockdown. Thus, MRP8/14 likely plays a role in exaggerated ISR in diabetes mellitus, and MRP8 inhibition may be useful in improving outcome after stent placement in diabetes mellitus.
糖尿病患者死亡的最常见原因是心血管疾病。患者经常接受血管介入治疗，如支架置入术。在非糖尿病患者中，使用药物洗脱支架已经减少了支架内再狭窄（ISR）的发生，但糖尿病患者的再狭窄和支架内血栓形成的发生率仍然较高。我们在 2 型糖尿病动物模型中研究了支架内再狭窄的发病机制。
在 Zucker 肥胖大鼠（ZFR）和野生型大鼠颈动脉中放置支架，并在手术后 14 天采集组织进行形态计量学分析。采集两组未放置支架的颈动脉进行微阵列分析。对大鼠和人主动脉内皮细胞（EC）进行体外凋亡、增殖和迁移实验。与野生型对照组相比，ZFR 支架放置后 14 天，内膜反应明显增强。与对照组相比，未放置支架的 ZFR 颈动脉中 MRP8 和 MRP14 上调。在暴露于高葡萄糖条件下的 EC 中，MRP8/14 的表达也升高。高葡萄糖浓度可损害 EC 功能，而 MRP8 过表达可模拟这种作用。高葡萄糖浓度暴露后，用 shRNA 敲低 MRP8 可显著恢复 EC 功能。用药理学阻断葡萄糖诱导的途径也抑制了葡萄糖暴露细胞中 MRP8 的表达。
高葡萄糖水平引起的 EC 功能障碍可通过 MRP8/14 过表达模拟，通过 MRP8 敲低逆转/预防。因此，MRP8/14 可能在糖尿病中支架内再狭窄的过度发生中起作用，抑制 MRP8 可能有助于改善糖尿病患者支架置入后的预后。
