Transgenic overexpression of matrix metalloproteinase-9 in macrophages attenuates the inflammatory response and improves left ventricular function post-myocardial infarction

Rogelio Zamilpa, Jessica Ibarra, Lisandra E. de Castro Brás, Trevi A. Ramirez, Nguyen Nguyen, Ganesh V. Halade, Jianhua Zhang, Qiuxia Dai, Tariq Dayah, Ying Ann Chiao, Wesley Lowell, Seema S. Ahuja, Jeanine D'Armiento, Yu Fang Jin, Merry L. Lindsey

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)599-608
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume53
Issue number5
DOIs
StatePublished - Nov 2012
Externally publishedYes

Keywords

  • Cardiac remodeling
  • Extracellular matrix
  • Inflammation
  • Macrophage
  • Matrix metalloproteinase-9
  • Myocardial infarction

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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