title: Transgenic overexpression of matrix metalloproteinase-9 in macrophages attenuates the inflammatory response and improves left ventricular function post-myocardial infarction.
abstract: Following myocardial infarction (MI), activated macrophages infiltrate into the necrotic myocardium as part of a robust pro-inflammatory response and secrete matrix metalloproteinase-9 (MMP-9). Macrophage activation, in turn, modulates the fibrotic response, in part by stimulating fibroblast extracellular matrix (ECM) synthesis. We hypothesized that overexpression of human MMP-9 in mouse macrophages would amplify the inflammatory and fibrotic responses to exacerbate left ventricular dysfunction. Unexpectedly, at day 5 post-MI, ejection fraction was improved in transgenic (TG) mice (25±2%) compared to the wild type (WT) mice (18±2%; p<0.05). By gene expression profiling, 23 of 84 inflammatory genes were decreased in the left ventricle infarct (LVI) region from the TG compared to WT mice (all p<0.05). Concomitantly, TG macrophages isolated from the LVI, as well as TG peritoneal macrophages stimulated with LPS, showed decreased inflammatory marker expression compared to WT macrophages. In agreement with attenuated inflammation, only 7 of 84 cell adhesion and ECM genes were increased in the TG LVI compared to WT LVI, while 43 genes were decreased (all p<0.05). These results reveal a novel role for macrophage-derived MMP-9 in blunting the inflammatory response and limiting ECM synthesis to improve left ventricular function post-MI.
authors.affiliation: San Antonio Cardiovascular Proteomics Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
authors.forename: Rogelio
authors.initials: R
authors.lastname: Zamilpa
authors.forename: Jessica
authors.initials: J
authors.lastname: Ibarra
authors.forename: Lisandra E
authors.initials: LE
authors.lastname: de Castro Brás
authors.forename: Trevi A
authors.initials: TA
authors.lastname: Ramirez
authors.forename: Nguyen
authors.initials: N
authors.lastname: Nguyen
authors.forename: Ganesh V
authors.initials: GV
authors.lastname: Halade
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Qiuxia
authors.initials: Q
authors.lastname: Dai
authors.forename: Tariq
authors.initials: T
authors.lastname: Dayah
authors.forename: Ying Ann
authors.initials: YA
authors.lastname: Chiao
authors.forename: Wesley
authors.initials: W
authors.lastname: Lowell
authors.forename: Seema S
authors.initials: SS
authors.lastname: Ahuja
authors.forename: Jeanine
authors.initials: J
authors.lastname: D'Armiento
authors.forename: Yu-Fang
authors.initials: YF
authors.lastname: Jin
authors.forename: Merry L
authors.initials: ML
authors.lastname: Lindsey
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D037502:Galectin 3 / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000201:enzymology* / Q000276:immunology / Q000503:physiopathology; D058628:Myofibroblasts / Q000378:metabolism; D009504:Neutrophils / Q000473:pathology; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D013318:Stroke Volume; D059467:Transcriptome; D016277:Ventricular Function, Left
chemical_list: D000943:Antigens, Differentiation; D015815:Cell Adhesion Molecules; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D037502:Galectin 3; D008070:Lipopolysaccharides; D018121:Receptors, Cytokine; C036763:monocyte-macrophage differentiation antigen; D020780:Matrix Metalloproteinase 9