title: Transgenic overexpression of macrophage matrix metalloproteinase-9 exacerbates age-related cardiac hypertrophy, vessel rarefaction, inflammation, and fibrosis.
abstract: 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 (allP< 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 (allP< 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 & NOTEWORTHYThe 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.
authors.affiliation: Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, Mississippi.|Division of Pathological Sciences, Department of Clinical Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Hiroe
authors.initials: H
authors.lastname: Toba
authors.affiliation: Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Presley L
authors.initials: PL
authors.lastname: Cannon
authors.affiliation: Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Andriy
authors.initials: A
authors.lastname: Yabluchanskiy
authors.affiliation: Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Rugmani Padmanabhan
authors.initials: RP
authors.lastname: Iyer
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York; and.
authors.forename: Jeanine
authors.initials: J
authors.lastname: D'Armiento
authors.affiliation: Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, Mississippi; mllindsey@umc.edu.|G. V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, Mississippi.
authors.forename: Merry L
authors.identifier: http://orcid.org/0000-0002-4090-0391
authors.initials: ML
authors.lastname: Lindsey
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D001808:Blood Vessels / Q000503:physiopathology*; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology*; D048429:Cell Size; D003094:Collagen / Q000378:metabolism; D004452:Echocardiography; D005260:Female; D005355:Fibrosis; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D008264:Macrophages; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000473:pathology
chemical_list: D003094:Collagen; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: MMP-9; aging; heart; inflammation