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.

GDF11 Protects against Endothelial Injury and Reduces Atherosclerotic Lesion Formation in Apolipoprotein E-Null Mice

“…Moreover, macrophages in plaques may secrete proteolytic enzymes, such as MMPs, which may digest the extracellular matrix and weaken the fibrous cap. 34 Indeed, AAV-GDF11 and recombinant GDF11 treatment significantly inhibited MMP-2 and MMP-9 protein expression in plaques in this study. Thus, there is a possible direct link between the decreased of macrophages and MMPs and increased of collagen as well as VSMCs in these lesions, indicating that GDF11 is a powerful cytokine for altering plaque components toward a stable plaque phenotype.…”

Angiotensin Inhibition Decreases Progression of Advanced Atherosclerosis and Stabilizes Established Atherosclerotic Plaques

“…34,39 Although elastin per se has been identified as a pivotal modulator of vascular response to injury, previous studies focused on macrophage-related elastolytic proteases. 40,41 This study makes the novel observations that AngII increases elastolysis by SMC in vitro and elastin breaks in the aortic media in vivo, although a contribution from macrophages and/or endothelial cells cannot be completely excluded. Our results also show that AngII antagonism prevents disruption of elastin and may even promote reconstitution of elastin through mechanisms that, at least in part, include modulation of the elastolytic capacity of VSMC.…”

Human CD68 promoter GFP transgenic mice allow analysis of monocyte to macrophage differentiation in vivo

“…The 2.9-kb human CD68 promoter and 83-bp first intron expression cassette has been used to direct expression of a range of different transgenes at a high level in macrophages in vivo, including SR-A, 34 interleukin-10, 28 PGC1 b, 35 matrix metallopeptidase-9, 36 FcgIIb, 37 Fox-P1, 38 acyloxyacyl hydrolase, 39 peroxisome proliferatoractivated receptor g, 40 and hPOP3. 41 In previous work, we used chromatin precipitation experiments to show that the ETS transcription factor family members PU.1, Elf-1, and Fli-1 are bound to the CD68 proximal promoter in myeloid THP-1 cells, but these transcription factors are not bound in primary B-lymphocytes because of interactions with IRF-4.…”