TY - JOUR
T1 - Elastin fragmentation inatheroscleroticmice leads to intraplaque neovascularization, plaque rupture, myocardial infarction, stroke, and sudden death
AU - Van der Donckt, Carole
AU - Van Herck, Jozef L.
AU - Schrijvers, Dorien M.
AU - Vanhoutte, Greetje
AU - Verhoye, Marleen
AU - Blockx, Ines
AU - Van Der Linden, Annemie
AU - Bauters, Dries
AU - Lijnen, Henri R.
AU - Sluimer, Judith C.
AU - Roth, Lynn
AU - Van Hove, Cor E.
AU - Fransen, Paul
AU - Knaapen, Michiel W.
AU - Hervent, Anne-Sophie
AU - De Keulenaer, Gilles W.
AU - Bult, Hidde
AU - Martinet, Wim
AU - Herman, Arnold G.
AU - De Meyer, Guido R. Y.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - 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.
AB - 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.
KW - Plaque rupture
KW - Angiogenesis
KW - Myocardial infarction
KW - Stroke
KW - Animal model
U2 - 10.1093/eurheartj/ehu041
DO - 10.1093/eurheartj/ehu041
M3 - Article
C2 - 24553721
VL - 36
SP - 1049-1058A
JO - European Heart Journal
JF - European Heart Journal
SN - 0195-668X
IS - 17
ER -