Advancing age is an independent risk factor for cardiovascular disease. Matrix metalloproteinase-9 (MMP-9) is secreted by macrophages and robustly increases in the left ventricle (LV) with age. The present study investigated the effect of MMP-9 overexpression in macrophages on cardiac aging. We compared 16-21 month old C57/BL6J wild type (WT) and transgenic (TG) male and female mice (n=15-20 /group). MMP-9 overexpression amplified the hypertrophic response to aging, as evidenced by increased LV wall thickness and myocyte cross sectional areas (p<0.05 for both). MMP-9 overexpression reduced LV expression of the angiogenesis-related factors intercellular adhesion molecule-1, integrins α3 and β3, platelet/endothelial cell adhesion molecule-1, thrombospondin-1, tenascin-c, and versican (all p<0.05). Concomitantly, the number of vessels in the TG was lower than WT LV (p<0.05). This led to a mismatch in the muscle to vessel ratio and resulted in increased cardiac inflammation. Out of 84 inflammatory genes analyzed, 16 genes increased in the TG compared to WT. Of the elevated genes, 14 were pro-inflammatory genes (all p<0.05). The increase in cardiac inflammation resulted in greater accumulation of interstitial collagen in TG (p<0.05). The changes occurred before global cardiac function deficits, as fractional shortening was similar between groups. In conclusion, overexpression of MMP-9 in macrophages resulted in exacerbated cardiac hypertrophy in the setting of vessel sarcopenia, which resulted in enhanced inflammation and fibrosis to enhance the cardiac aging phenotype.
- matrix metalloproteinases-9
- Copyright © 2016, American Journal of Physiology-Heart and Circulatory Physiology