Abstract 546: Investigation Of The Role Of LRP1 Patient Mutations On Abdominal Aortic Aneurysms

LRP1 (low density lipoprotein receptor-related protein 1) is a large endocytic receptor that binds over 100 structurally unrelated ligands. Our lab has demonstrated that a sm22 promoter-driven, smooth muscle specific knock-out of LRP1 (smLRP1-/-) results in aortic aneurysms in mice due to fragmentation and degradation of the elastic fibers, further implicating LRP1 in vascular development. Furthermore, the identification of a patient with abdominal aortic aneurysm (AAA) harboring missense mutations in LRP1 has allowed for investigations into the role of LRP1 in aneurysm formation. Utilizing a combination of biochemical and proteomic techniques, we sought to understand the role of these mutations in cellular function. By means of a receptor-ligand binding assay, we quantified the internalization and degradation of 125 I-activated alpha-2-macroglobulin (a2M*) in LRP1-deficient cells transfected with mutant LRP1 and aortic smooth muscle cells isolated from a patient with an abdominal aortic aneurysm and LRP1 missense mutations. The results showed defects in LRP1-mediated internalization of a 2 M* in LRP1 variants when compared to wild type LRP1. Furthermore, through extensive proteomic analysis of primary patient cells harboring these mutations, multiple dysregulated pathways of interest have been identified along with elevated levels of MMP-1 in the cultured media. In total, our data highlights the biochemical deficits in different variants of LRP1 that may contribute to the pathogenesis of AAA. Pinpointing the role of LRP1 in aneurysm mechanisms will allow for non-invasive interventions to be employed before aortic rupture.