title: Elastin fragmentation in atherosclerotic mice leads to intraplaque neovascularization, plaque rupture, myocardial infarction, stroke, and sudden death.
abstract: OBJECTIVE
  There is a need for animal models of plaque rupture. We previously reported that elastin fragmentation, due to a mutation (C1039G(+/-)) in the fibrillin-1 (Fbn1) gene, promotes atherogenesis and a highly unstable plaque phenotype in apolipoprotein E deficient (ApoE(-/-)) mice on a Western-type diet (WD). Here, we investigated whether plaque rupture occurred in ApoE(-/-)Fbn1(C1039G+/-) mice and was associated with myocardial infarction, stroke, and sudden death.
  
  
  RESULTS
  Female ApoE(-/-)Fbn1(C1039G+/-) and ApoE(-/-) mice were fed a WD for up to 35 weeks. Compared to ApoE(-/-) mice, plaques of ApoE(-/-)Fbn1(C1039G+/-) mice showed a threefold increase in necrotic core size, augmented T-cell infiltration, a decreased collagen I content (70 ± 10%), extensive neovascularization, intraplaque haemorrhage, and a significant increase in matrix metalloproteinase-2, -9, -12, and -13 expression or activity. Plaque rupture was observed in 70% of ascending aortas and in 50% of brachiocephalic arteries of ApoE(-/-)Fbn1(C1039G+/-) mice. In ApoE(-/-) mice, plaque rupture was not seen in ascending aortas and only in 10% of brachiocephalic arteries. Seventy percent of ApoE(-/-)Fbn1(C1039G+/-) mice died suddenly, whereas all ApoE(-/-) mice survived. ApoE(-/-)Fbn1(C1039G+/-) mice showed coronary plaques and myocardial infarction (75% of mice). Furthermore, they displayed head tilt, disorientation, and motor disturbances (66% of cases), disturbed cerebral blood flow (73% of cases; MR angiograms) and brain hypoxia (64% of cases), indicative of stroke.
  
  
  CONCLUSIONS
  Elastin fragmentation plays a key role in plaque destabilization and rupture. ApoE(-/-)Fbn1(C1039G+/-) mice represent a unique model of acute plaque rupture with human-like complications.
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium carole.vanderdonckt@uantwerpen.be.
authors.forename: Carole
authors.initials: C
authors.lastname: Van der Donckt
authors.affiliation: Division of Cardiology, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Jozef L
authors.initials: JL
authors.lastname: Van Herck
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
authors.forename: Dorien M
authors.initials: DM
authors.lastname: Schrijvers
authors.affiliation: Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium.
authors.forename: Greetje
authors.initials: G
authors.lastname: Vanhoutte
authors.affiliation: Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium.
authors.forename: Marleen
authors.initials: M
authors.lastname: Verhoye
authors.affiliation: Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium.
authors.forename: Ines
authors.initials: I
authors.lastname: Blockx
authors.affiliation: Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium.
authors.forename: Annemie
authors.initials: A
authors.lastname: Van Der Linden
authors.affiliation: Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Dries
authors.initials: D
authors.lastname: Bauters
authors.affiliation: Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Henri R
authors.initials: HR
authors.lastname: Lijnen
authors.affiliation: Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
authors.forename: Judith C
authors.initials: JC
authors.lastname: Sluimer
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
authors.forename: Lynn
authors.initials: L
authors.lastname: Roth
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
authors.forename: Cor E
authors.initials: CE
authors.lastname: Van Hove
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Fransen
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
authors.forename: Michiel W
authors.initials: MW
authors.lastname: Knaapen
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Hervent
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
authors.forename: Gilles W
authors.initials: GW
authors.lastname: De Keulenaer
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
authors.forename: Hidde
authors.initials: H
authors.lastname: Bult
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Martinet
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
authors.forename: Arnold G
authors.initials: AG
authors.lastname: Herman
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
authors.forename: Guido R Y
authors.initials: GR
authors.lastname: De Meyer
mesh_terms: D000818:Animals; D001011:Aorta; D001057:Apolipoproteins E / Q000172:deficiency; D015415:Biomarkers / Q000378:metabolism; D016122:Brachiocephalic Trunk; D006332:Cardiomegaly / Q000209:etiology / Q000503:physiopathology; D017536:Carotid Artery, Common; D002560:Cerebrovascular Circulation / Q000502:physiology; D003645:Death, Sudden / Q000209:etiology*; D066273:Diet, Western; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism*; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D006470:Hemorrhage / Q000209:etiology; D002534:Hypoxia, Brain / Q000209:etiology / Q000503:physiopathology; D051379:Mice; D008840:Microfilament Proteins / Q000172:deficiency; D055806:Microvessels; D009203:Myocardial Infarction / Q000209:etiology* / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000503:physiopathology; D009422:Nervous System Diseases / Q000209:etiology / Q000503:physiopathology; D058226:Plaque, Atherosclerotic / Q000209:etiology* / Q000503:physiopathology; D012422:Rupture, Spontaneous / Q000209:etiology / Q000503:physiopathology; D020521:Stroke / Q000209:etiology*; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000503:physiopathology; D054392:Adipokines
chemical_list: D001057:Apolipoproteins E; D015415:Biomarkers; D004549:Elastin; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse
keywords: Angiogenesis; Animal model; Myocardial infarction; Plaque rupture; Stroke