Abstract 3197: A Novel Small Molecule Inhibitor Targeted Towards MMP9 Significantly Slows Down Formation of abdominal Aortic Aneurysms in a Rat Model
The objective of the present study is to identify new therapeutics for abdominal aortic aneurysms (AAA). We used the MMP9 enzyme as our first target against which to develop novel small molecule inhibitors, since
its expression was highly elevated in the aneurysmal tissue based on microarray studies,
it has been studied extensively and found to be a key player in the aneurysm growth and rupture, and
there are no known selective and potent MMP9 inhibitors in existence for MMP9. Our approach is structural chemical-genetic ligand design to identify small molecule inhibitors, which bind to the catalytic domain of MMP9. The compounds were tested in the elastase-perfusion model for AAA in rats. Animals receiving only the vehicle (DMSO; n=5) developed AAAs, while rats treated with doxycycline (n=19) and our novel inhibitor called 26SH (n=7) had significantly smaller increase in aortic diameter 14 days following elastase-perfusion (comparison to DMSO group: p=.0274 for doxycycline group and p=.0096 for 26SH group). Histological analysis showed that elastin in the medial wall (Verhoeff’s van Gieson stain) was degraded in DMSO aortas, whereas it remained intact in the aortas of doxycycline and 26SH-treated rats. The inflammatory cells were reduced in doxycycline and 26SH groups compared to controls. The presence of macrophages and neutrophils was confirmed by immunohistochemical methods which showed that there were fewer inflammatory cells in the doxycycline and 26SH-treated animals. MMP9 staining using rabbit anti-rat MMP9 antibody was more evident in DMSO aortas compared to doxycycline and 26SH-treated rats. Most of MMP9 colocalized with smooth muscle cells in the media and adventitia in the DMSO group. Taken together these results demonstrate that the novel small molecule inhibitor of MMP9, 26SH, was effective in slowing down the growth of AAA in the rat model.