Elastin is one of the abundant structural proteins of the extracellular matrix of cardiovascular tissue. Elastin degeneration and calcification occurs in a number of cardiovascular diseases including arteriosclerosis, calcific aortic stenosis, bioprosthetic heart valve calcification, human aortic and pulmonary allografts, and in patients with diabetes or renal failure undergoing dialysis. The exact mechanisms of elastin calcification are not completely understood and no clinical therapy is available to prevent or reverse elastin calcification. The hypothesis being pursued is that elastin calcification process is governed by three major events: matrix degeneration and remodeling, osteogenesis, and apoptosis. We propose to continue our mechanistic studies of elastin calcification in two animal models: rat subdermal implantation of purified aortic elastin (developed by the PI), and clinically relevant rat abdominal aortic injury model.
Aim I : Hypothesis: The onset and progression of elastin calcification occurs through specific remodeling, osteogenic and apoptosis pathways. Approach: Early and late events that accompany elastin calcification in a rat abdominal aorta periadventitial injury model will be studied. Mineral analysis will be accompanied by characterization of the extent and significance of matrix metalloproteinase (MMP)-mediated elastin degradation, presence of elastin peptides and downstream effects of elastin peptides, including activation of the elastin/laminin receptor (ELR), cell differentiation, expression of bone genes such as core binding factor-1 (CBFA) and bone matrix formation (bone morphogenic proteins, osteocalcin, osteopontin) and apoptosis.
Aim II : Hypothesis: Targeted blocking of early pathogenic events, including matrix remodeling, osteogenic and apoptosis will inhibit or limit elastin calcification. Approach: To block initial calcification events, we will use site-specific delivery systems in both experimental animal models concomitantly with initiation of calcification, and follow the course of elastin calcification and expression of remodeling / osteogenic / apoptotic signals. Blocking of elastin degradation/remodeling will be achieved by 1) gene silencing by delivery of MMP-2 and MMP-9 siRNA and 2) by blocking ELR activity with specific antibody. Osteogenesis will be blocked by site specific delivery of CBFA-1 siRNA or adenoviral vector carrying noggin (a BMP antagonist) gene. Long-term objective of our program is to understand the mechanistic pathways of elastin calcification so that it can be prevented or reversed. The following specific aims will be pursued in this continuation program.
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