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Updated: May 19, 2026
Isolation of Functional Cardiac Immune Cells
Published on: December 5, 2011
Transgenic overexpression of matrix metalloproteinase-9 in macrophages attenuates the inflammatory response and
Rogelio Zamilpa1, Jessica Ibarra, Lisandra E de Castro Brás
1San Antonio Cardiovascular Proteomics Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
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.
Insights
Overexpressing matrix metalloproteinase-9 (MMP-9) in macrophages after myocardial infarction (MI) unexpectedly improved heart function. This study reveals MMP-9
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Biology
Background:
- Macrophages infiltrate the myocardium post-myocardial infarction (MI), driving inflammation and secreting matrix metalloproteinase-9 (MMP-9).
- Macrophage-derived MMP-9 influences fibroblast activity and extracellular matrix (ECM) synthesis, impacting cardiac remodeling.
- The precise role of macrophage-derived MMP-9 in post-MI left ventricular function remains incompletely understood.
Purpose of the Study:
- To investigate the functional consequences of macrophage-specific MMP-9 overexpression on left ventricular dysfunction following myocardial infarction.
- To determine how elevated MMP-9 levels in macrophages affect inflammatory and fibrotic responses in the infarcted heart.
Main Methods:
- Generation of transgenic (TG) mice overexpressing human MMP-9 in macrophages.
- Induction of myocardial infarction (MI) in TG and wild-type (WT) mice.
- Assessment of cardiac function (ejection fraction) and gene expression profiling of inflammatory and ECM-related genes in the left ventricle infarct (LVI) region at day 5 post-MI.
- Analysis of inflammatory marker expression in isolated macrophages from TG and WT mice.
Main Results:
- TG mice exhibited improved ejection fraction at day 5 post-MI compared to WT mice.
- Gene expression profiling revealed decreased inflammatory gene expression in the LVI of TG mice.
- Macrophages from TG mice, both in the LVI and peritoneal cavity, displayed reduced inflammatory marker expression.
- Cell adhesion and ECM gene expression were significantly downregulated in the LVI of TG mice.
Conclusions:
- Macrophage-derived MMP-9 plays a novel, protective role in the post-MI heart.
- Overexpression of MMP-9 in macrophages attenuates the inflammatory response and limits excessive ECM synthesis.
- These effects collectively contribute to improved left ventricular function after myocardial infarction.
