title: Network analysis of human in-stent restenosis.
abstract: BACKGROUND
  Recent successes in the treatment of in-stent restenosis (ISR) by drug-eluting stents belie the challenges still faced in certain lesions and patient groups. We analyzed human coronary atheroma in de novo and restenotic disease to identify targets of therapy that might avoid these limitations.
  
  
  RESULTS
  We recruited 89 patients who underwent coronary atherectomy for de novo atherosclerosis (n=55) or in-stent restenosis (ISR) of a bare metal stent (n=34). Samples were fixed for histology, and gene expression was assessed with a dual-dye 22,000 oligonucleotide microarray. Histological analysis revealed significantly greater cellularity and significantly fewer inflammatory infiltrates and lipid pools in the ISR group. Gene ontology analysis demonstrated the prominence of cell proliferation programs in ISR and inflammation/immune programs in de novo restenosis. Network analysis, which combines semantic mining of the published literature with the expression signature of ISR, revealed gene expression modules suggested as candidates for selective inhibition of restenotic disease. Two modules are presented in more detail, the procollagen type 1 alpha2 gene and the ADAM17/tumor necrosis factor-alpha converting enzyme gene. We tested our contention that this method is capable of identifying successful targets of therapy by comparing mean significance scores for networks generated from subsets of the published literature containing the terms "sirolimus" or "paclitaxel." In addition, we generated 2 large networks with sirolimus and paclitaxel at their centers. Both analyses revealed higher mean values for sirolimus, suggesting that this agent has a broader suppressive action against ISR than paclitaxel.
  
  
  CONCLUSIONS
  Comprehensive histological and gene network analysis of human ISR reveals potential targets for directed abrogation of restenotic disease and recapitulates the results of clinical trials of existing agents.
authors.affiliation: Division of Cardiovascular Medicine, Falk CVRC, Stanford University, Stanford, Calif 94305, USA. euan@stanford.edu
authors.forename: Euan A
authors.initials: EA
authors.lastname: Ashley
authors.forename: Rossella
authors.initials: R
authors.lastname: Ferrara
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: King
authors.forename: Aditya
authors.initials: A
authors.lastname: Vailaya
authors.forename: Allan
authors.initials: A
authors.lastname: Kuchinsky
authors.forename: Xuanmin
authors.initials: X
authors.lastname: He
authors.forename: Blake
authors.initials: B
authors.lastname: Byers
authors.forename: Ulrich
authors.initials: U
authors.lastname: Gerckens
authors.forename: Stefan
authors.initials: S
authors.lastname: Oblin
authors.forename: Anya
authors.initials: A
authors.lastname: Tsalenko
authors.forename: Angela
authors.initials: A
authors.lastname: Soito
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Spin
authors.forename: Raymond
authors.initials: R
authors.lastname: Tabibiazar
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Connolly
authors.forename: John B
authors.initials: JB
authors.lastname: Simpson
authors.forename: Eberhard
authors.initials: E
authors.lastname: Grube
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000502:physiology; D000072198:ADAM17 Protein; D000328:Adult; D000368:Aged; D003094:Collagen / Q000037:antagonists & inhibitors / Q000235:genetics; D024042:Collagen Type I; D003324:Coronary Artery Disease / Q000473:pathology; D023903:Coronary Restenosis / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D008875:Middle Aged; D015607:Stents
chemical_list: D024042:Collagen Type I; D003094:Collagen; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human