Abstract 11188: Identification of Key Modulators Involved in Aortic Aneurysm Formation In Fibulin-4 Deficient Mice
Purpose of Research: Fibulin4 (Fbln4) is a secreted extracellular matrix (ECM) protein, expressed in blood vessels and associated with microfibrils surrounding elastic fibers. We previously showed smooth muscle cell (SMC)-specific deletion of Fbln4 in vivo (Fbln4SMKO) leads to changes in SMC phenotypes, hyper-proliferation and ascending aortic aneurysm. Although aneurysms are completely prevented by inhibition of the angiotensin II (AngII) pathway in Fbln4SMKO mice, the molecular mechanism of aneurysm formation is still under investigation.
Methodology: To identify key modulators involved in aneurysm formation, we compared protein profiles between Fbln4SMKO ascending aorta and that of wild-type (WT). The early stage of aneurysm formation was evaluated by histology. Protein expression profiles were obtained from WT and Fbln4SMKO ascending aortae at each stage of aneurysm development (postnatal day 1 (P1), P7, P14, and P30) by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). Several differentially expressed proteins were identified by mass spectrometry and validated using qPCR and Western blot analysis. To examine if these proteins are associated with aneurysm phenotypes, we evaluated the expression of candidate proteins in Fbln4SMKO animals treated with losartan (angiotensin II type 1 receptor blocker) and compared with untreated animals.
Results: Histologically, focal lesion of SMC proliferation was noticeable at P7 and became more evident at P14 with a thickened aortic media. 2D-DIGE showed that identified proteins are mainly involved in actin dynamics and cofilin is activated by cofilin phosphatase, Slingshot (SSH-1L), in Fbln4SMKO ascending aorta. Furthermore, prenatal treatment with losartan effectively prevented elevation of SSH and cofilin activity. Implications: Our study indicated that the phenotypic change of SMCs occurred after P7 and cofilin activity may play an important role in aneurysm formation in the Fbln4SMKO aorta. Future study will shed light on the molecular mechanism of aneurysm formation mediated by cofilin activation in the Fbln4 deficient SMCs.
- © 2013 by American Heart Association, Inc.