Impaired fibrillin-1 function promotes features of plaque instability in apolipoprotein E-deficient mice
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Faculty of Medicine and Health Sciences
New York, N.Y.
Circulation / American Heart Association. - New York, N.Y.
, p. 2478-2487
University of Antwerp
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.