Abstract 15990: Macrophage Migration Inhibitory Factor Directly Influences Aortic Aneurysm Development in a Murine Model
Background: Based on our previous findings that AAA lesions have increased MIF levels in humans and that serum MIF levels correlate with aneurysm size and expansion rate, we hypothesized that MIF directly influences AAA development.
Methods and Results: Indeed, MIF deficiency dramatically reduced elastase-induced AAA in Balb/C male mice. MIF deficiency reduced aneurysm development and inflammation in the lesions 14 days post-elastase treatment. None of the 11 MIF-/- mice developed AAA, defined as an increase in aortic diameter (AD) ≥100% (calculated as the difference between the pre-perfusion diameter and final diameter), while all WT mice developed AAA lesions (n=4). MIF deficiency also decreased inflammatory cells in AAA lesions. The content of macrophages (percent of Mac3-positive area to the entire lesion area, 2-fold, p<0.01) and of CD4-positive T cells (number of cells per 1mm2, 5-fold, p=0.05) was significantly lower in MIF KO lesions compared to WT lesions. As we anticipated based on MIF's ability to induce elastolytic cathepsin expression and activity, we found better-preserved elastica in MIF KO compared to WT AAA lesions (2-fold, p<0.003). MIF-/- lesions had lower levels of elastolytic activity compared to WT AAA, but similar to the levels of activity after the addition of cathepsin inhibitor E64, as determined by in situ zymography with a fluorogenic DQ elastin. MIF raised elastolytic cathepsin expression and activity, as shown by studies in macrophages from MIF-/- mice and recombinant (rMIF)-treated human EC in vitro. Because angiogenesis plays an important role in AAA and correlates with AAA growth, we tested the ability of aortic EC to form sprouts in an aortic ring assay, and found that MIF-/- aortas develop 8-fold smaller EC growing areas compared to WT aortas (p<0.001). MIF deficiency also decreased proliferation of inflammatory cells in the lesions (7-fold, p=0.047). Proliferation of SMC isolated from MIF KO aorta was ~5-fold lower than WT SMC, and could be restored in part by rMIF.
Conclusions: MIF deficiency diminishes elastase-induced AAA formation in mice. We showed a direct effect of rMIF on cathepsin-related elastolysis, angiogenesis, and cell proliferation in vitro. These findings point to MIF as a therapeutic target in AAA.
- © 2011 by American Heart Association, Inc.