A selective matrix metalloproteinase-12 inhibitor retards atherosclerotic plaque development in apolipoprotein E-knockout mice

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.