Abstract 16783: Matrix Metalloproteinase-9 Deletion Alters the Age-Associated Inflammation Profile by Upregulating M2 Macrophage Polarization
In the setting of myocardial infarction, matrix metalloproteinase-9 (MMP-9) deletion reduces macrophage infiltration into the left ventricle (LV) and attenuates LV remodeling. We recently showed that LV MMP-9 levels increase with age, and MMP-9 deletion attenuates cardiac aging by modifying the extracellular matrix response to prevent diastolic dysfunction. However, the effects of MMP-9 deletion on the inflammatory component of cardiac aging have not been investigated. We evaluated wild-type (WT) and MMP-9 null mice of four age groups: young (6-9 months), middle aged (12-15 months), old (18-24 months), and senescent (> 25 months). Biclustering analysis for 84 inflammatory genes revealed a unique aging inflammatory pattern. With age, the WT LV showed no significant changes in expression of macrophage M1 markers but did show decreases in M2 marker expression. In contrast, MMP-9 deletion promoted the downregulation of M1 markers and prevented the decrease in M2 markers. Immunohistochemical staining for Mac-3 showed increased macrophage content in the LVs of senescent WT mice compared to young mice, and this increase was not affected by MMP-9 deletion. To determine if MMP-9 deletion regulated macrophage activation, we isolated peritoneal macrophages from young and senescent WT and MMP-9 null mice and compared their macrophage polarization profiles. Interestingly, senescent MMP-9 null macrophages showed similar levels of M1 markers (Ccl3, IL1β, and TNFα), but higher levels of M2 markers (CD163 and IL10), compared to WT counterparts. Consistently, senescent null LV showed higher gene expression of the M2 marker Ym1. In conclusion, MMP-9 deletion alters the age-associated inflammation profile by upregulating M2 macrophage polarization in the aging LVs, which may be the underlying mechanism of attenuating aging-induced LV fibrosis and diastolic dysfunction.
- © 2013 by American Heart Association, Inc.