Abstract 17580: Matrix Metalloproteinase-12 Inhibition Exacerbates Cardiac Dysfunction and Stimulates Inflammation Post-Myocardial Infarction in Mice
MMP-12 deficiency reduces macrophage infiltration and diminishes the capacity to degrade extracellular matrix (ECM), but whether MMP-12 inhibition post-myocardial infarction (MI) is effective as a therapeutic strategy has not been evaluated. We evaluated the left ventricle (LV) over the first week post-MI. MMP-12 gene expression increased robustly only at day 1 (p<0.05 compared to day 0 control; n=6/ group). Adult male C57BL/6J mice (3-6 months old, n=60) were subjected to left coronary artery ligation. Osmotic pumps with saline or MMP-12 inhibitor (MMP-12i; 0.5 mg/kg/day) were inserted subcutaneously at 3h post-MI, and the mice were sacrificed at days 1 and 7 post-MI. Infarct area was similar in the saline (57±1%) and MMP-12i (55±1%, p=0.93) groups at day 1 post-MI, indicating similar initial injury and consistent with intervention starting at 3h post-MI. The day 7 infarct areas were also similar between the two groups. Survival rates were 33% (12/36) for saline and 50% for the MMP-12i (12/24; p=0.29). There was a 33±1% reduction in MMP-12 activity in the inhibitor group at day 1 post-MI, compared to activity levels in the saline group (p<0.05). By echocardiography, MMP-12 inhibition worsened LV function at d7 post-MI, as exhibited by larger LV volumes, increased wall thinning, decreased ejection fraction, and increased hypertrophy and remodeling indices in the inhibitor group (all p<0.05). Out of 84 inflammatory genes examined in the infarct region, 12 pro-inflammatory genes were increased 0.5-16 fold in the MMP-12i MI group compared to the saline MI group (p<0.05), indicating an overall increase in inflammation with MMP-12 inhibition. Out of 84 ECM genes examined in the infarct region, 4 genes (CD44, TGF-βi, Itgb2 and thrombospondin-2) were 0.1-0.4 fold downregulated in the MMP-12i group suggesting a reduced ECM response. Protein levels of CD44, a known stimulator of inflammation, were also reduced by 50±1% in the infarcted LV of MMP-12i group compared to the saline group (p<0.05). In conclusion, MMP-12 inhibition post-MI exacerbates LV dysfunction and stimulates inflammation, in part by attenuating CD44 expression to prolong the inflammatory phase.
- © 2013 by American Heart Association, Inc.