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 6

Representative lesions from apoE–/– mice with macrophage overexpression of MMP-9 G100L demonstrate multiple features of ruptured plaques.

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Representative lesions from apoE–/– mice with macrophage overexpression ...
Representative brachiocephalic lesions from apoE–/– mice transplanted with HSCs transduced with CD68S–MMP-9 G100L (A–K) or CD68S–MMP-9 (L–O) were stained with the following: Carstairs stain (A–C, F–H, L, and M), Gomori aldehyde fuchsin (GAF) (J, K, and O); a fibrin/fibrinogen antibody (D, I, and N); and control IgG (E). Original magnification, ×10 (A, F, J, L, and O); ×20 (B, D, E, G, K, M, and N); ×40 (C, H, and I). (A–E) The lesion shoulder (A, inset) from a mouse receiving HSCs transduced with CD68S–MMP-9 G100L shows fibrin deposition with Carstairs staining (B and C, black arrowheads), distinct from SMCs (B and C, white arrowheads). Fibrin deposition was confirmed by positive staining with anti-fibrin/fibrinogen antibody (D) but not with nonimmune control IgG (E). The staining with the anti-fibrin/fibrinogen antibody was more extensive than Carstairs-positive fibrin areas, but this is consistent with the antibody recognizing multiple forms of the protein (B–D). (F–J) A lesion from a different mouse transplanted with HSCs transduced with CD68S–MMP-9 G100L demonstrates rupture of the thinned fibrous cap (F, inset; J, arrowhead) with rbcs within the lesion (G, arrowheads). It also shows modest Carstairs staining of mature thrombin deposits (H, arrowheads), which were confirmed by fibrin/fibrinogen staining (I, arrowheads). Areas of fibrous cap disruption are apparent with GAF (J, yellow asterisks), but no evidence of elastin destruction in the medial layers is observed (K). (L–O) Lesion from a mouse transplanted with MMP-9–transduced HSCs shows Carstairs staining of SMCs (M, white arrowheads) but no evidence of fibrin deposits, although positive areas are seen with the antibody recognizing fibrin/fibrinogen (N). GAF staining of this lesion (O) shows elastin (arrowhead) covering the shoulder.