A proteomics study of protein changes in the extracellular matrix (ECM) of aorta cells revealed several proteins associated with changes to blood vessel walls, leading to abdominal aortic aneurysm (AAA). One of the hallmarks of AAA is the pathological remodeling of the aortic ECM; however, past proteomic investigations of AAA looked at cellular proteins, not specifically those of the ECM. The team at King’s British Heart Foundation Centre at King’s College, London, used two-pass mass spectrometry to identify and quantify proteins in the ECM of aorta cells from patients with AAA. By comparing results with normal aortic ECM proteins, they identified those potentially involved in the disease process.1
The team recognized they needed to overcome problems associated with looking at the proteins in the ECM that past proteomic investigations did not. First, they had to ensure the separation of cellular proteins from more scarce ECM proteins. Second, they needed to develop a method for solubilizing the ECM, which due to crosslinking, glycosylation, and aggregation, is relatively less soluble than other cellular materials. Third, they had to separate new proteins laid down by the natural repair process from degrading proteins in the original ECM. To avoid these problems, they developed a new solubility-based protein sub-fractionation method. The new procedure promotes extraction of new ECM proteins, reduces contamination with cellular proteins, and enhances solubility.1
The new method proved productive, and the team identified new targets for potential drug-based therapeutic intervention. Notably, in the AAA samples, they found the fragmentation of several proteins, including pereostin, collagen XII, thrombospondin 2, fibronectin, and aortic carboxypeptidase-like protein (ACLP). At the same time, they found upregulation of the proteolytic, matrix metalloproteinase 12 (MMP-12), which had been previously identified as significant in tissue remodeling and ECM degradation. MMP-12 lyses all the above proteins, except fibronectin, and its effect on ACLP was very marked in the AAA tissue samples in which ACLP is almost completely destroyed in areas affected by inflammation.1
Currently, the only interventions for AAA include open surgery and endovascular repair. Clinicians monitor AAA size and general patient health to determine whether or not to intervene to prevent rupture. At 40%, the postoperative mortality for a ruptured AAA is high.2
It is possible that drug therapies targeting the inhibition of MMP-12 could lead to a reduction in damage to the ECM, resulting in smaller AAAs and fewer deaths due to rupture.
1. Didangelos, A., et al. (2011) ‘Extracellular matrix composition and remodeling in human abdominal aortic aneurysms: a proteomics approach‘, Molecular and Cellular Proteomics, 10 (8), (p. M111.008128)