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Title
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Elastin fragmentation in atherosclerotic mice leads to intraplaque neovascularization, plaque rupture, myocardial infarction, stroke, and sudden death
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Author
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Abstract
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| 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−/−Fbn1C1039G+/− mice and was associated with myocardial infarction, stroke, and sudden death. Methods and results Female ApoE−/−Fbn1C1039G+/− and ApoE−/− mice were fed a WD for up to 35 weeks. Compared to ApoE−/− mice, plaques of ApoE−/−Fbn1C1039G+/− 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−/−Fbn1C1039G+/− mice. In ApoE−/− mice, plaque rupture was not seen in ascending aortas and only in 10% of brachiocephalic arteries. Seventy percent of ApoE−/−Fbn1C1039G+/− mice died suddenly, whereas all ApoE−/− mice survived. ApoE−/−Fbn1C1039G+/− 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−/−Fbn1C1039G+/− mice represent a unique model of acute plaque rupture with human-like complications. |
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Language
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English
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Source (journal)
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European heart journal. - London
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Publication
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London
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2015
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ISSN
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0195-668X
[Print]
1522-9645
[Online]
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DOI
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10.1093/EURHEARTJ/EHU041
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Volume/pages
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36
:17
(2015)
, p. 1049-1058A
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ISI
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000354452900013
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Pubmed ID
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24553721
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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