Elastin fragmentation inatheroscleroticmice leads to intraplaque neovascularization, plaque rupture, myocardial infarction, stroke, and sudden death

Carole Van der Donckt*, Jozef L. Van Herck, Dorien M. Schrijvers, Greetje Vanhoutte, Marleen Verhoye, Ines Blockx, Annemie Van Der Linden, Dries Bauters, Henri R. Lijnen, Judith C. Sluimer, Lynn Roth, Cor E. Van Hove, Paul Fransen, Michiel W. Knaapen, Anne-Sophie Hervent, Gilles W. De Keulenaer, Hidde Bult, Wim Martinet, Arnold G. Herman, Guido R. Y. De Meyer

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

103 Citations (Web of Science)

Abstract

Aims 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. Methods and 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(-/-)Fbn1C(1039G+/-) mice. In ApoE(-/-) mice, plaque rupture was not seen in ascending aortas and only in 10% of brachiocephalic arteries. Seventy percent of ApoE(-/-) Fbn1C(1039G+/-) 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(-/-)Fbn1C(1039G+/-) mice represent a unique model of acute plaque rupture with human-like complications.
Original languageEnglish
Pages (from-to)1049-1058A
JournalEuropean Heart Journal
Volume36
Issue number17
DOIs
Publication statusPublished - 1 May 2015

Keywords

  • Plaque rupture
  • Angiogenesis
  • Myocardial infarction
  • Stroke
  • Animal model

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