Abstract 15699: Matrix Metalloproteinase-9 Overexpression in Macrophages Improves Ventricular Function by Regulating the Inflammatory and Fibrotic Responses Post-Myocardial Infarction
Macrophage activation post-myocardial infarction (MI) influences the extent of left ventricular remodeling. Post-MI, activated macrophages infiltrate into the injured myocardium to provide a robust pro-inflammatory stimulus that includes matrix metalloproteinase-9 (MMP-9) up regulation. Subsequently, the degree of macrophage activation modulates the fibrotic response, in part by activating fibroblast extracellular matrix (ECM) synthesis. We hypothesized that overexpression of MMP-9 in macrophages would increase the degree of inflammation and increase ECM gene expression levels in the left ventricle (LV) to enhance the development of LV dysfunction. In this study, we evaluated, at day 5 post-MI, wild type (WT, n=16) and transgenic (TG, n=28) mice that specifically over-express human MMP-9 in macrophages. We assessed LV function by echocardiography and profiled inflammatory and ECM gene expression by quantitative RT-PCR gene arrays (Qiagen). Both WT and TG groups had identical infarct sizes of 49±2% in each group. Surprisingly, end systolic volume post-MI increased in WT mice (69±4 µl) but was attenuated, not exacerbated, in the TG group (56±4 µl; p<0.05). Additionally, ejection fraction was improved in the TG mice post-MI (25±2%) compared with the WT mice post-MI (18±2%; p<0.05). By gene expression profiling, 23 out of 84 inflammatory genes were increased in the WT mice post-MI compared to day 0 controls and TG mice post-MI (all p<0.05). These genes included IL-1β, mcp-1, ccr-1, -2, -3 and -5, and cxcl10. In agreement with a decrease in inflammation, only 7 of 84 cell adhesion and ECM genes were increased in the TG infarct, compared with 43 genes in the WT infarct (all p<0.05). Among the ECM and adhesion genes increased in the WT but not in the TG were mmp-2, -3, -7, -8, -10, 12, -13 and -15 (all p<0.05). On the contrary, ecm 1, fibronectin, mmp-14, periostin and tenascin were among the 7 genes that increased in the TG compared to the WT (all p<0.05). These results reveal a novel role for macrophage-derived MMP-9 in blunting the inflammatory response and promoting ECM synthesis to improve left ventricular function post-MI.
- © 2011 by American Heart Association, Inc.