Abstract 15787: Aorta Proteome Profiling Uncovers Enhanced Arterial Aging In Aneurismal Fibulin-4 Mutant Mice
Fibulin-4 is a secreted glycoprotein, which is expressed in medial layers of blood vessels. All six reported fibulin-4 patients suffer from cardiovascular complications including aortic aneurysms, arterial tortuosity and stenosis and elastin abnormalities. We have engineered fibulin-4 mouse models that express reduced levels of the fibulin-4 protein and develop aortic abnormalities similar to fibulin-4 patients. Interestingly, heterozygous fibulin-4+/R mice show mild symptoms of aneurysm formation like ballooning of the right subclavian artery and a slightly dilated aorta, while the homozygous fibulin-4R/R mice show elongated and 2-3 fold dilated ascending aorta. To get insight into the underlying molecular pathways involved in aneurysm formation and response to aortic failure, we determined the aorta proteome of fibulin-4+/R and fibulin-4R/R animals. A full un-biased qualitative MS/MS proteomic screen of the aorta protein extracts identified 192 unique proteins in fibulin-4+/R and 220 unique proteins in fibulin-4R/R mice compared to fibulin-4+/+ animals, of which 80 were commonly present in both mutants. Next, an overlay of the aorta tissue proteome and transcriptome was made to find a limited set of biomarkers that were identified by both gene and protein expression analysis of the fibulin-4+/Rand fibulin-4R/R mice. In the fibulin-4R/R mice a limited set of biomarkers pointed towards altered regulation of 17-beta-estradiol and TNF-alpha pathways. Interestingly, the 17-beta-estradiol pathway was also found in the fibulin-4+/R mice. The signaling molecule 17-beta estradiol is a metabolite known to deregulate production of reactive oxygen species (ROS) by poorly understood mechanisms. Notably both these regulatory pathways are also deregulated by oxidative stress, which is a hallmark of aging and age related cardiovascular diseases. To address altered cell signaling and cell death in the aneurismal aorta we have performed TUNEL staining, and to validate differential production of ROS and antioxidants we have indirectly quantified ROS by superoxide staining. These results uncover new regulatory pathways likely to be associated with enhanced arterial aging in aneurismal fibulin-4 mice.
- © 2010 by American Heart Association, Inc.