Transgenic overexpression of macrophage matrix metalloproteinase-9 exacerbates age-related cardiac hypertrophy, vessel rarefaction, inflammation, and fibrosis

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 312; no. 3; pp. H375 - H383
• Main Authors: Toba, Hiroe, Cannon, Presley L., Yabluchanskiy, Andriy, Iyer, Rugmani Padmanabhan, D’Armiento, Jeanine, Lindsey, Merry L.
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.03.2017
• Series: Advances in Cardiovascular Geroscience
• Subjects: Aging; Aging - pathology; Animals; Blood Vessels - physiopathology; Cardiomegaly - diagnostic imaging; Cardiomegaly - genetics; Cardiomegaly - physiopathology; Cardiovascular disease; Cell Size; Collagen - metabolism; Echocardiography; Enzymes; Female; Fibrosis; Genes; Genotype & phenotype; Heart Ventricles - pathology; Humans; Inflammation - physiopathology; Macrophages; Male; Matrix Metalloproteinase 9 - genetics; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocytes, Cardiac - pathology; Risk factors; aging; inflammation; MMP-9; heart
• ISSN: 0363-6135; 1522-1539; 1522-1539
• DOI: 10.1152/ajpheart.00633.2016

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- to 21-mo-old C57BL/6J 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 ICAM-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 with WT (all P < 0.05). Of the elevated genes, 14 were proinflammatory genes. The increase in cardiac inflammation resulted in greater accumulation of interstitial collagen in TG ( P < 0.05). Fractional shortening was similar between groups, indicating that global cardiac function was still preserved at this age. In conclusion, overexpression of MMP-9 in macrophages resulted in exacerbated cardiac hypertrophy in the setting of vessel rarefaction, which resulted in enhanced inflammation and fibrosis to augment the cardiac-aging phenotype. Our results provide evidence that macrophage-derived MMP-9 may be a therapeutic target in elderly subjects. NEW & NOTEWORTHY The present study was the first to use mice with transgenic overexpression of matrix metalloproteinase-9 (MMP-9) in macrophages to examine the effects of macrophage-derived MMP-9 on cardiac aging. We found that an elevation in macrophage-derived MMP-9 induced a greater age-dependent cardiac hypertrophy and vessel rarefaction phenotype, which enhanced cardiac inflammation and fibrosis. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/macrophage-mmp-9-accelerates-cardiac-aging/ .