title: A role for MRP8 in in stent restenosis in diabetes.
abstract: 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.
  
  
  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.
authors.affiliation: Regenerative Medicine Institute, REMEDI, National University of Ireland Galway, Ireland.
authors.forename: A
authors.initials: A
authors.lastname: Stocca
authors.forename: D
authors.initials: D
authors.lastname: O'Toole
authors.forename: N
authors.initials: N
authors.lastname: Hynes
authors.forename: S O
authors.initials: SO
authors.lastname: Hynes
authors.forename: K
authors.initials: K
authors.lastname: Mashayekhi
authors.forename: L
authors.initials: L
authors.lastname: McGinley
authors.forename: E
authors.initials: E
authors.lastname: O'Connell
authors.forename: C
authors.initials: C
authors.lastname: Coleman
authors.forename: S
authors.initials: S
authors.lastname: Sultan
authors.forename: A
authors.initials: A
authors.lastname: Duffy
authors.forename: S
authors.initials: S
authors.lastname: Tunev
authors.forename: T
authors.initials: T
authors.lastname: O'Brien
mesh_terms: D017130:Angioplasty / Q000009:adverse effects* / Q000295:instrumentation*; D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000378:metabolism; D040501:Calgranulin A / Q000235:genetics / Q000378:metabolism*; D040502:Calgranulin B / Q000235:genetics / Q000378:metabolism; D002339:Carotid Arteries / Q000378:metabolism* / Q000473:pathology; D016893:Carotid Stenosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications*; D003925:Diabetic Angiopathies / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D058426:Neointima / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D051381:Rats; D011924:Rats, Zucker; D015607:Stents; D014162:Transfection
chemical_list: D001786:Blood Glucose; D040501:Calgranulin A; D040502:Calgranulin B