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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\u201320\/group). MMP-9 overexpression amplified the hypertrophic response to aging, as evidenced by increased LV wall thickness and myocyte cross-sectional areas ( P &lt; 0.05 for both). MMP-9 overexpression reduced LV expression of the angiogenesis-related factors ICAM-1, integrins \u03b13 and \u03b23, platelet\/endothelial cell adhesion molecule-1, thrombospondin-1, tenascin-c, and versican (all P &lt; 0.05). Concomitantly, the number of vessels in the TG was lower than WT LV ( P &lt; 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 &lt; 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 &lt; 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.<\/jats:p><jats:p>NEW &amp; 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.<\/jats:p><jats:p>Listen to this article's corresponding podcast at http:\/\/ajpheart.podbean.com\/e\/macrophage-mmp-9-accelerates-cardiac-aging\/ .<\/jats:p>","DOI":"10.1152\/ajpheart.00633.2016","type":"journal-article","created":{"date-parts":[[2016,12,24]],"date-time":"2016-12-24T02:32:21Z","timestamp":1482546741000},"page":"H375-H383","source":"Crossref","is-referenced-by-count":69,"title":["Transgenic overexpression of macrophage matrix metalloproteinase-9 exacerbates age-related cardiac hypertrophy, vessel rarefaction, inflammation, and fibrosis"],"prefix":"10.1152","volume":"312","author":[{"given":"Hiroe","family":"Toba","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, Mississippi;"},{"name":"Division of Pathological Sciences, Department of Clinical Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Presley L.","family":"Cannon","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, Mississippi;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andriy","family":"Yabluchanskiy","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, Mississippi;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rugmani Padmanabhan","family":"Iyer","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, Mississippi;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanine","family":"D\u2019Armiento","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4090-0391","authenticated-orcid":false,"given":"Merry L.","family":"Lindsey","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, Mississippi;"},{"name":"G. 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