Impaired Fibrillin-1 Function Promotes Features of Plaque Instability in Apolipoprotein E–Deficient Mice

Abstract

Background— Arterial stiffness has been associated with an increased cardiovascular risk. The aim of this study was to investigate the interaction between arterial stiffness and atherosclerosis. Methods and Results— Mice with a mutation (C1039G +/− ) in the fibrillin-1 gene leading to fragmentation of the elastic fibers were crossbred with apolipoprotein E–deficient (ApoE −/− ) mice. Subsequently, ApoE −/− and ApoE −/− C1039G +/− mice were fed a Western-type diet for 10 or 20 weeks. Our results show that the interaction between arterial stiffness and atherosclerosis is bidirectional. On the one hand, arterial stiffness in ApoE −/− C1039G +/− mice increased more rapidly in the presence of atherosclerotic plaques. On the other hand, arterial stiffness promoted the development of larger and more unstable plaques in ApoE −/− C1039G +/− mice. The plaque area at the aortic root was increased 1.5- and 2.1-fold in ApoE −/− C1039G +/− mice after 10 and 20 weeks of Western-type diet, respectively. After 10 weeks of Western-type diet, plaques of ApoE −/− C1039G +/− mice showed increased apoptosis of smooth muscle cells, which was associated with a decrease in collagen content, an enlargement of the necrotic core, and an increase in macrophages. After 20 weeks of Western-type diet, the number of buried fibrous caps was increased in atherosclerotic lesions of ApoE −/− C1039G +/− mice, not only at the level of the aortic valves but also in the brachiocephalic artery and in the upper, middle, and lower thoracic aorta. Furthermore, acute plaque rupture was observed. Conclusion— These results indicate that fragmentation of the elastic fibers leads to increased vascular stiffness, which promotes features of multifocal plaque instability.

Is arterial wall-strain stiffening an additional process responsible for atherosclerosis in coronary bifurcations?: an in vivo study based on dynamic CT and MRI

“…1B of Van Herck et al (42)]. In addition, their results showed a significant correlation between increase of arterial wall stiffness in atherosclerotic mice and plaque development.…”

“…Interestingly, the animal study performed by Van Herck et al (42) showed that an increase of arterial stiffness promotes plaque development. In their study, the effect of increased arterial stiffness on atherosclerosis was investigated by feeding a Western-type diet for 10 or 20 wk apolipoprotein E (ApoE)-deficient (ApoE Ϫ/Ϫ ) and ApoE Ϫ/Ϫ C1039G Ϫ/Ϫ mice with mutation in the fibrillin-1 gene.…”

Chronic intermittent mental stress promotes atherosclerotic plaque vulnerability, myocardial infarction and sudden death in mice

“…To this end, apolipoprotein E deficient mice (ApoE À/À ) with a heterozygous mutation in the fibrillin-1 gene (Fbn1 C1039Gþ/À ) were used. Recently, we reported that this unique mouse model shows an accelerated plaque progression, spontaneous plaque ruptures, myocardial infarction and sudden death [32,33]. Therefore, it is an adequate model to study the effects of mental stress on plaque vulnerability and the occurrence of myocardial infarctions.…”

Pathology of human plaque vulnerability: Mechanisms and consequences of intraplaque haemorrhages

“…For these reasons, most relevant data on IPH comes from clinical studies and analysis of human tissues. Nevertheless, a model resulting from a cross between apoE KO and fibrillin KI (Marfan) mice has been reported to develop important intraplaque neo-angiogenesis with the presence of IPH [15,16].…”