Abstract 16525: A Genetic Link Between Thoracic and Abdominal Aortic Disease Revealed by Fibulin-4 Deficiency
Deficiency of the FBLN4 gene, encoding the extracellular matrix protein Fibulin-4, induces thoracic aortic aneurysm formation. In Fibulin-4 knockdown mice, we have identified fibulin-4 dose dependent TGF-β dysregulation and matrix metalloproteinases (MMP) as key markers in thoracic aneurysm formation. In humans, however, aneurysms usually develop in the abdominal aorta, and are associated with aging and atherosclerosis as opposed to thoracic aortic aneurysms (TAA's) which commonly have a genetic cause and are detected in young patients. Aneurysmatic and atherosclerotic arterial diseases have common risk factors and similarities in biological processes. However, the two diseases have opposite outcomes, i.e. dilatation versus stenosis. To investigate the molecular mechanisms differentiating aneurysmatic from atherosclerotic arterial disease, we crossbred Fibulin-4 knockdown with ApoE knockout (ApoE-/-) mice and put these double mutant animals on a western type diet for 10 and 20 weeks. We analyzed the localization and composition of plaques and its effect on the aortic wall by in vivo ultrasound hemodynamics measurements and in vivo MMP activity imaging. Plaque composition was subsequently analyzed through quantitative oil-red-O, collagen and macrophage analysis. After 10 weeks of high fat diet, ApoE-/- Fibulin-4R/R mice displayed TAA's with a complete different pattern of plaque deposition caused by altered hemodynamics as a consequence of aortic regurgitation. Surprisingly, ApoE-/- Fibulin-4+/R mice displayed increased MMP activity in the abdominal aorta and increased plaque formation at the level of the visceral arteries as compared with ApoE-/- Fibulin-4+/+ and ApoE+/+ Fibulin-4+/R mice. Thus, a mild deficiency in fibulin-4, a gene known for inherited TAA disease,affects MMP activity and alters both plaque deposition and composition in the abdominal aorta and can possibly result in predisposition for AAA. This is the first murine model reflecting the common human condition of coexistent formation of aneurysms and atherogenesis.
- © 2011 by American Heart Association, Inc.