A Selective Matrix Metalloproteinase-12 Inhibitor Retards Atherosclerotic Plaque Development in Apolipoprotein E–Knockout Mice
- 1 March 2011
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Arteriosclerosis, Thrombosis, and Vascular Biology
- Vol. 31 (3), 528-535
- https://doi.org/10.1161/atvbaha.110.219147
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. Conclusion— 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.Keywords
This publication has 44 references indexed in Scilit:
- Monocyte/Macrophage Suppression in CD11b Diphtheria Toxin Receptor Transgenic Mice Differentially Affects Atherogenesis and Established PlaquesCirculation Research, 2007
- Genomics of Foam Cells and Nonfoamy Macrophages From Rabbits Identifies Arginase-I as a Differential Regulator of Nitric Oxide ProductionArteriosclerosis, Thrombosis, and Vascular Biology, 2007
- Effect of broad-spectrum matrix metalloproteinase inhibition on atherosclerotic plaque stabilityCardiovascular Research, 2006
- Suppression of Atherosclerotic Plaque Progression and Instability by Tissue Inhibitor of Metalloproteinase-2Circulation, 2006
- Macrophage Metalloelastase Accelerates the Progression of Atherosclerosis in Transgenic RabbitsCirculation, 2006
- Pathology of the Vulnerable PlaqueJournal of the American College of Cardiology, 2006
- Development of Selective Inhibitors and Substrate of Matrix Metalloproteinase-12Published by Elsevier BV ,2006
- Resolution of apoptosis in atherosclerotic plaque by dietary modification and statin therapy.2005
- Matrix Metalloproteinase-13/Collagenase-3 Deletion Promotes Collagen Accumulation and Organization in Mouse Atherosclerotic PlaquesCirculation, 2005
- Dual Role of Matrix Metalloproteinases (Matrixins) in Intimal Thickening and Atherosclerotic Plaque RupturePhysiological Reviews, 2005