Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice
Peter J. Gough, … , Paul T. Wille, Elaine W. Raines
Peter J. Gough, … , Paul T. Wille, Elaine W. Raines
Published January 4, 2006
Citation Information: J Clin Invest. 2006;116(1):59-69. https://doi.org/10.1172/JCI25074.
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Research Article Cardiology

Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice

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.

Authors

Peter J. Gough, Ivan G. Gomez, Paul T. Wille, Elaine W. Raines

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Figure 7

Multiple sites with characteristics of plaque rupture in the aortae of mice with macrophages expressing MMP-9 G100L.

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Multiple sites with characteristics of plaque rupture in the aortae of m...
Longitudinal sections of the aortic arch, its branches (minus the brachiocephalic artery), and thoracic aortae stained with Carstairs were evaluated in apoE–/– mice transplanted with HSCs transduced with CD68S–MMP-9 G100L (A–F) or CD68S–MMP-9 (G–J). These lesions represent the most severely affected mice in each group. Original magnification, ×10 (A, B, and G); ×20 (H–J); ×40 (C–F). (A–F) A mouse receiving HSCs transduced with CD68S–MMP-9 G100L had at least 13 different regions in which lesions showed evidence of previous plaque rupture (A, asterisks). Rupture was most apparent and frequent at the downstream side of the lesion in the lesser curvature as illustrated at higher magnifications (B–F). rbcs are embedded in a fibrin-rich matrix detected by Carstairs stain (C) and confirmed by anti-fibrin/fibrinogen immunohistochemistry (D), while other areas are primarily fibrin rich (E, Carstairs stain; F, fibrin/fibrinogen immunostaining). Features of plaque rupture were observed in all mice in this group (n = 7), with at least 5 regions in the lesions in each aorta and its branches. (G–J) This aorta was from 1 of only 2 of the 8 total mice receiving HSCs transduced with CD68S–MMP-9 that showed any areas with features of plaque rupture in longitudinal sections. The 2 regions boxed in G with characteristics of plaque rupture are shown at higher power (H–J). rbcs and a fibrin deposit are seen in H (black arrowhead), while the lesion in I and J shows fibrin deposition by Carstairs (I) that is confirmed by anti-fibrin/fibrinogen staining (J).