Characterization and validation of ApoE-/- Abcc6-/- mice as an animal model for rupture of atherosclerotic plaques.

Rupture of atherosclerotic plaques remains the main cause of acute cardiovascular syndromes and death. The need for novel plaque stabilizing therapies is high, but adequate animal models of plaque rupture are lacking. We recently discovered that apolipoprotein E knock-out (ApoE-/-) mice with a heterozygous mutation (C1039G+/-) in the fibrillin-1 (Fbn1) gene show elastin fragmentation and arterial stiffness which leads to acute plaque rupture, myocardial infarction, stroke and sudden death. Although elastin fragmentation seems to trigger plaque rupture in ApoE-/- Fbn1C1039G+/- mice, there is currently insufficient evidence that supports this hypothesis. Therefore, the present research proposal aims to use ApoE-/-Abcc6-/- mice representing another mouse model of elastin degradation, yet via an alternative mechanism that involves progressive mineralization of the vessel wall. After confirmation of elastin fragmentation in ApoE-/-Abcc6-/- mice, the key objectives of the project are:1) Characterization of ApoE-/-Abcc6-/- mice for atherosclerotic plaque development and rupture. 2) Validation of this mouse model for plaque rupture with established plaque stabilizing drugs (statins).3) Study of the effects of everolimus as a novel potential plaque stabilizing therapy.Overall, this research proposal could provide better insights in the mechanisms of plaque rupture, and would allow quick evaluation of potential plaque stabilizing therapies on genuine clinical end points of plaque rupture in mice.

Keywords:MOUSE MODELS, PLAQUE RUPTURE, PHARMACOLOGY, ATHEROSCLEROSIS

Disciplines:Cardiac and vascular medicine, Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences