title: A novel mouse model of atherosclerotic plaque instability for drug testing and mechanistic/therapeutic discoveries using gene and microRNA expression profiling.
abstract: BACKGROUND
  The high morbidity/mortality of atherosclerosis is typically precipitated by plaque rupture and consequent thrombosis. However, research on underlying mechanisms and therapeutic approaches is limited by the lack of animal models that reproduce plaque instability observed in humans.
  
  
  OBJECTIVE
  Development and use of a mouse model of plaque rupture that reflects the end stage of human atherosclerosis.
  
  
  RESULTS
  On the basis of flow measurements and computational fluid dynamics, we applied a tandem stenosis to the carotid artery of apolipoprotein E-deficient mice on high-fat diet. At 7 weeks postoperatively, we observed intraplaque hemorrhage in ≈50% of mice, as well as disruption of fibrous caps, intraluminal thrombosis, neovascularization, and further characteristics typically seen in human unstable plaques. Administration of atorvastatin was associated with plaque stabilization and downregulation of monocyte chemoattractant protein-1 and ubiquitin. Microarray profiling of mRNA and microRNA (miR) and, in particular, its combined analysis demonstrated major differences in the hierarchical clustering of genes and miRs among nonatherosclerotic arteries, stable, and unstable plaques and allows the identification of distinct genes/miRs, potentially representing novel therapeutic targets for plaque stabilization. The feasibility of the described animal model as a discovery tool was established in a pilot approach, identifying a disintegrin and metalloprotease with thrombospondin motifs 4 (ADAMTS4) and miR-322 as potential pathogenic factors of plaque instability in mice and validated in human plaques.
  
  
  CONCLUSIONS
  The newly described mouse model reflects human atherosclerotic plaque instability and represents a discovery tool toward the development and testing of therapeutic strategies aimed at preventing plaque rupture. Distinctly expressed genes and miRs can be linked to plaque instability.
authors.affiliation: Baker IDI Heart & Diabetes Institute, Melbourne, Australia.
authors.forename: Yung-Chih
authors.initials: YC
authors.lastname: Chen
authors.forename: Anh Viet
authors.initials: AV
authors.lastname: Bui
authors.forename: Jeannine
authors.initials: J
authors.lastname: Diesch
authors.forename: Richard
authors.initials: R
authors.lastname: Manasseh
authors.forename: Christian
authors.initials: C
authors.lastname: Hausding
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rivera
authors.forename: Izhak
authors.initials: I
authors.lastname: Haviv
authors.forename: Alex
authors.initials: A
authors.lastname: Agrotis
authors.forename: Nay Min
authors.initials: NM
authors.lastname: Htun
authors.forename: Jeremy
authors.initials: J
authors.lastname: Jowett
authors.forename: Christoph Eugen
authors.initials: CE
authors.lastname: Hagemeyer
authors.forename: Ross D
authors.initials: RD
authors.lastname: Hannan
authors.forename: Alex
authors.initials: A
authors.lastname: Bobik
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Peter
mesh_terms: D000818:Animals; D016893:Carotid Stenosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D058226:Plaque, Atherosclerotic / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D035683:MicroRNAs
keywords: acute myocardial infarction; angiogenesis; animal models of human disease; arterial thrombosis; atherosclerosis; gene expression profiling; inflammation; microRNA profiling; plaque rupture