Abstract 13389: Early Matrix Metalloproteinase-9 Inhibition Stimulates Neutrophil Infiltration and Delays Neutrophil Apoptosis Post-Myocardial Infarction in Mice

Matrix metalloproteinase-9 (MMP-9) increases in the first week post-MI, and targeted deletion of the MMP-9 gene attenuates cardiac remodeling post-myocardial infarction (MI), but whether MMP-9 inhibition early post-MI is effective therapeutic strategy has not been evaluated. Adult male C57BL/6J mice (3-6 months old, n=80) were subjected to coronary artery ligation. Saline or MMP-9 inhibitor (MMP-9i; 0.03 μg/day) was delivered at 3 h post-MI, and the mice were sacrificed at days 1 or 7 post-MI. Infarct area was similar in the saline (57±1%) and MMP-9i (55±1%) groups (p=0.22), indicating equal initial injury. The 7 day post-MI survival rates showed no significant difference between saline and MMP-9i groups (p=0.54). MMP-9 inhibition resulted in a 31±1% reduction in MMP-9 activity at day 1 post-MI (p<0.05 vs. saline). Surprisingly, MMP-9 inhibition worsened LV function at day 7 post-MI, as shown by ejection fractions of 13±1% for saline vs. 8±1% for MMP-9i (p<0.05). Of 84 inflammatory genes examined in the day 7 infarct, 15 pro-inflammatory genes were increased and one decreased in the MMP-9i group (all p<0.05 vs. saline). Because MMP-9i showed increased inflammation at day 7, we measured neutrophil numbers. The saline group showed increased neutrophils at day 1, with numbers declining by day 7 due to induction of apoptosis. In MMP-9i, neutrophils were 2-fold higher at day 1 and persisted at day 7 for an 18-fold difference from saline, indicating prolonged neutrophil presence. Isolated blood neutrophils stimulated with active MMP-9 showed increased levels of pro-apoptotic markers Bcl and Bax compared to unstimulated control (both p<0.05). Interestingly, neutrophils stimulated with active MMP-9 and treated with MMP-9i showed increased levels of anti-apoptotic markers Mcl and Xiap (both p<0.05) compared to MMP-9 treated cells. This suggests that prolonged neutrophil presence with the MMP-9 inhibition was due to a dramatic reduction in neutrophil apoptosis. In conclusion, MMP-9 inhibition starting immediately post-MI decreased neutrophil apoptosis leading to increased inflammation and resulting in exacerbated LV dysfunction. Cat: 515 - Apoptosis and Necrosis