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Updated: May 11, 2026
Depletion and Reconstitution of Macrophages in Mice
Published on: August 1, 2012
Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice
Peter J Gough1, Ivan G Gomez, Paul T Wille
1Department of Pathology, University of Washington, Harborview Medical Center, Seattle, Washington 98104-2499, USA. peter.j.gough@gsk.com
Abstract:
The majority of acute clinical manifestations of atherosclerosis are due to the physical rupture of advanced atherosclerotic plaques. It has been hypothesized that macrophages play a key role in inducing plaque rupture by secreting proteases that destroy the extracellular matrix that provides physical strength to the fibrous cap. Despite reports detailing the expression of multiple proteases by macrophages in rupture-prone regions, there is no direct proof that macrophage-mediated matrix degradation can induce plaque rupture. We aimed to test this hypothesis by retrovirally overexpressing the candidate enzyme MMP-9 in macrophages of advanced atherosclerotic lesions of apoE-/- mice. Despite a greater than 10-fold increase in the expression of MMP-9 by macrophages, there was only a minor increase in the incidence of plaque fissuring. Subsequent analysis revealed that macrophages secrete MMP-9 predominantly as a proform, and this form is unable to degrade the matrix component elastin. Expression of an autoactivating form of MMP-9 in macrophages in vitro greatly enhances elastin degradation and induces significant plaque disruption when overexpressed by macrophages in advanced atherosclerotic lesions of apoE-/- mice in vivo. These data show that enhanced macrophage proteolytic activity can induce acute plaque disruption and highlight MMP-9 as a potential therapeutic target for stabilizing rupture-prone plaques.
Insights
Macrophages can trigger plaque rupture in atherosclerosis by releasing matrix-degrading enzymes. Activating matrix metalloproteinase-9 (MMP-9) in macrophages significantly increased plaque disruption, identifying MMP-9 as a therapeutic target for stabilizing vulnerable plaques.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Atherosclerosis Research
Background:
- Atherosclerotic plaque rupture is a major cause of acute cardiovascular events.
- Macrophages within plaques are suspected to mediate rupture by secreting matrix-degrading proteases.
- Direct evidence linking macrophage-derived matrix degradation to plaque rupture is lacking.
Purpose of the Study:
- To investigate if macrophage-mediated matrix degradation can induce atherosclerotic plaque rupture.
- To determine the role of matrix metalloproteinase-9 (MMP-9) in macrophage-induced plaque instability.
Main Methods:
- Overexpression of MMP-9 in macrophages within advanced atherosclerotic lesions of apoE-/- mice using retroviral vectors.
- Assessment of plaque fissuring and MMP-9 expression levels.
- In vitro studies to evaluate the activity of different MMP-9 forms on elastin degradation.
- In vivo studies using an autoactivating form of MMP-9 in macrophages.
Main Results:
- Overexpressing standard MMP-9 in macrophages led to only minor plaque fissuring.
- Macrophages primarily secrete MMP-9 as an inactive proform, which cannot degrade elastin.
- An autoactivating form of MMP-9 significantly enhanced elastin degradation in vitro.
- In vivo overexpression of autoactivating MMP-9 in macrophages induced significant plaque disruption in apoE-/- mice.
Conclusions:
- Macrophage-derived proteolytic activity, specifically active MMP-9, can directly induce acute atherosclerotic plaque disruption.
- MMP-9 requires activation to effectively degrade extracellular matrix components like elastin.
- Targeting MMP-9 activation presents a potential therapeutic strategy for stabilizing rupture-prone atherosclerotic plaques.
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