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

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 comp...

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Vydáno v:American journal of physiology. Heart and circulatory physiology Ročník 312; číslo 3; s. H375
Hlavní autoři: Toba, Hiroe, Cannon, Presley L, Yabluchanskiy, Andriy, Iyer, Rugmani Padmanabhan, D'Armiento, Jeanine, Lindsey, Merry L
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 01.03.2017
Témata:
Aging - pathology
Animals
Blood Vessels - physiopathology
Cardiomegaly - diagnostic imaging
Cardiomegaly - genetics
Cardiomegaly - physiopathology
Cell Size
Collagen - metabolism
Echocardiography
Female
Fibrosis
Heart Ventricles - pathology
Humans
Inflammation - physiopathology
Macrophages
Male
Matrix Metalloproteinase 9 - genetics
Mice
Mice, Inbred C57BL
Mice, Transgenic
Myocytes, Cardiac - pathology
aging
inflammation
MMP-9
heart
ISSN:1522-1539, 1522-1539
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Shrnutí: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 ( = 15-20/group). MMP-9 overexpression amplified the hypertrophic response to aging, as evidenced by increased LV wall thickness and myocyte cross-sectional areas ( < 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 < 0.05). Concomitantly, the number of vessels in the TG was lower than WT LV ( < 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 < 0.05). Of the elevated genes, 14 were proinflammatory genes. The increase in cardiac inflammation resulted in greater accumulation of interstitial collagen in TG ( < 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. 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.
Bibliografie:ObjectType-Article-1
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ISSN:1522-1539
1522-1539
DOI:10.1152/ajpheart.00633.2016