PMC

Human matrix metalloproteinase-9 (MMP-9) was expressed in macrophages isolated from the left ventricles of macrophage MMP-9 transgenic (TG; n = 7) but not wild-type (WT; n = 6) mice. Macrophages were isolated from 16- to 21-mo-old mice. Gene expression was normalized to Hprt1 and is shown as 2^−ΔCt. Data are expressed as means ± SE.

Overexpression of macrophage matrix metalloproteinase-9 (MMP-9) increased collagen content in the left ventricles (LVs). LV sections were stained with Picrosirius Red (PSR) and quantified. A: representative images of PSR-stained LV sections from wild-type (WT; n = 10; left) and macrophage MMP-9 transgenic (TG; n = 8; right) mice. Original scale bars, 50 μm. B: percentage of the collagen area/total area, showing an increased collagen content in the old TG compared with WT. Data are expressed as means ± SE.

Macrophage matrix metalloproteinase-9 (MMP-9) overexpression increased myocyte hypertrophy in 16- to 21-mo-old mice. A: representative images of hematoxylin-eosin-stained sections from the left ventricles (LVs) of wild-type (WT; n = 9; left) and macrophage MMP-9 transgenic (TG; n = 6; right) mice. Original scale bars, 50 μm. B: myocyte cross-sectional areas were quantified by measuring the area of 5 random cells/section for a total of 25 myocytes/LV. Graph shows greater myocyte size in old TG compared with WT. Data are expressed as means ± SE.

Mechanistic diagram showing the hypothesized influence of macrophage matrix metalloproteinase-9 (MMP-9) in cardiac aging. In wild-type mice, myocyte hypertrophy occurs with advancing age, which increases oxygen demand. MMP-9 suppresses the increase in angiogenic stimuli in an aged heart, leading to insufficient angiogenesis and microcirculation. Imbalance of oxygen supply triggers an inflammatory response. Cardiac inflammation induces the production of fibrogenic cytokines, leading to accumulation of collagens and adverse remodeling. Transgenic overexpression of MMP-9 in macrophages exacerbates these effects of MMP-9 in cardiac aging, leading to greater inflammation and fibrosis, which may cause feedback to myocyte hypertrophy.

Transgenic (TG) overexpression of macrophage matrix metalloproteinase-9 (MMP-9) increased age-related vessel rarefaction. Blood vessels in the left ventricles (LVs) of 16- to 21-mo-old mice were stained with Griffonia (Bandeiraea) simplicifolia lectin I (GSL-I) and quantified. A: representative images showing GSL-I-positive cells (black stain) in the LVs of wild-type (WT; n = 6; left) and macrophage MMP-9 TG (n = 7; right) mice. Original scale bars, 100 μm. B: percentage of GSL-I-positive area/total area, showing that vessel area was smaller in old TG compared with WT. Data are expressed as means ± SE.