A Selective Matrix Metalloproteinase-12 Inhibitor Retards Atherosclerotic Plaque Development in Apolipoprotein E-Knockout Mice

JL Johnson, L Devel, B Czarny, SJ George, CL Jackson, V Rogakos, F Beau, A Yiotakis, AC Newby, V Dive

Research output: Contribution to journalArticle (Academic Journal)peer-review

111 Citations (Scopus)

Abstract

OBJECTIVE: Matrix metalloproteinase (MMP)-12 has been implicated in plaque progression and instability and is also amenable to selective inhibition. In this study, we investigated the influence of a greater than 10-fold selective synthetic MMP-12 inhibitor on plaque progression in the apolipoprotein E knockout mouse model of atherosclerosis. METHODS AND RESULTS: A phosphinic peptide (RXP470.1) that is a potent, selective murine MMP-12 inhibitor significantly reduced atherosclerotic plaque cross-sectional area by approximately 50% at 4 different vascular sites in male and female apolipoprotein E knockout mice fed a Western diet. Furthermore, RXP470.1 treatment resulted in less complex plaques with increased smooth muscle cell:macrophage ratio, less macrophage apoptosis, increased cap thickness, smaller necrotic cores, and decreased incidence of calcification. Additional in vitro and in vivo findings indicate that attenuated monocyte/macrophage invasion and reduced macrophage apoptosis probably underlie the beneficial effects observed on atherosclerotic plaque progression with MMP-12 inhibitor treatment. CONCLUSIONS: Our data demonstrate that a selective MMP-12 inhibitor retards atherosclerosis development and results in a more fibrous plaque phenotype in mice. Our study provides proof of principle to motivate translational work on MMP-12 inhibitor therapy in humans.
Translated title of the contributionA Selective Matrix Metalloproteinase-12 Inhibitor Retards Atherosclerotic Plaque Development in Apolipoprotein E-Knockout Mice
Original languageEnglish
Pages (from-to)528 - 535
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume31
Issue number3
Early online date6 Jan 2011
DOIs
Publication statusPublished - Mar 2011

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