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Updated: May 24, 2026
A Murine Model of Stent Implantation in the Carotid Artery for the Study of Restenosis
Published on: May 14, 2013
A role for MRP8 in in stent restenosis in diabetes
1Regenerative Medicine Institute, REMEDI, National University of Ireland Galway, Ireland.
Insights
Diabetic patients experience higher rates of in-stent restenosis (ISR) after vascular stenting. Myeloid-related protein 8/14 (MRP8/14) over-expression in endothelial cells contributes to this exaggerated response, suggesting MRP8 inhibition as a potential therapeutic strategy.
Area of Science:
- Cardiovascular Research
- Diabetes Mellitus Pathophysiology
- Vascular Biology
Background:
- Cardiovascular disease is the leading cause of death in diabetes mellitus patients.
- Drug-eluting stents reduce in-stent restenosis (ISR) in non-diabetics, but diabetic patients still face higher restenosis and stent thrombosis rates.
- Understanding the pathogenesis of ISR in diabetes is crucial for improving stenting outcomes.
Purpose of the Study:
- To investigate the mechanisms underlying exaggerated in-stent restenosis (ISR) in a type 2 diabetes mellitus animal model.
- To explore the role of myeloid-related proteins (MRPs) in diabetes-associated vascular dysfunction and ISR.
Main Methods:
- Stent placement in Zucker Fatty rats (diabetic model) and wild-type rats, followed by morphometric analysis of carotid arteries.
- Microarray analysis of unstented carotid arteries and in vitro assays (apoptosis, proliferation, migration) on endothelial cells (ECs) exposed to high glucose.
- Investigated the effect of MRP8/14 up-regulation, down-regulation (shRNA), and pharmacological inhibition on EC function.
Main Results:
- Diabetic rats exhibited an exaggerated intimal response to stent placement compared to controls.
- MRP8 and MRP14 were upregulated in diabetic rat arteries and in ECs exposed to high glucose.
- High glucose impaired EC function, an effect mimicked by MRP8 over-expression and reversed by MRP8 knockdown.
Conclusions:
- Endothelial cell dysfunction induced by high glucose is linked to MRP8/14 over-expression.
- MRP8/14 plays a significant role in the exaggerated ISR observed in diabetes mellitus.
- Inhibiting MRP8 may offer a therapeutic approach to improve outcomes after stenting in diabetic patients.
Objective:
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.
Methods And Results:
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.
Conclusions:
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.
