Abstract 3765: Inhibition of MMP-12 Retards Atherosclerotic Plaque Development and Increases Stability in the Apolipoprotein E-Deficient Mouse
Matrix metalloproteinases (MMPs) form a large family of 23 enzymes that collectively can degrade all components of the extracellular matrix. We have shown previously that knocking out MMP-12 results in smaller plaques that rupture less frequently in the brachiocephalic artery of apoE knockout mice. Furthermore, treatment with a broad-spectrum MMP inhibitor fails to exert a beneficial effect on plaque development and stability. Against this background, and in view of the widespread interest in developing specific MMP inhibitors for the prevention of plaque rupture, we have investigated the effect on plaque development and stability of a phosphinic peptide that acts as potent murine MMP-12 inhibitor (RXP470.1, Ki 4 nM) which has a reduced potency of 2–3 orders towards other MMPs and ADAMs. Male and female apoE knockout mice were fed a Western diet, and at termination with pressure perfusion fixation the aortic root, proximal aorta, brachiocephalic artrery and thoracic aorta were removed and analysed by computerised morphometry. For RXP470.1-treatment, there was an 8 week fat-feeding period prior to 4 weeks of drug administration via Alzet osmotic mini-pump at a rate of 0.25μl/hour at a dose of 1.66 nmol/L, leading to a ~100 nM concentration of RXP407.1 in plasma that fully blocks MMP-12 activity, whilst sparing other MMPs. Control animals received osmotic mini-pumps containing vehicle alone. Atherosclerotic plaque cross-sectional area was significantly reduced at all four sites. Moreover, atherogenesis was significantly retarded by 50% (p<0.05). Furthermore, RXP470.1-treatment resulted in favourable changes in characteristics associated with plaque stability, e.g. increased smooth muscle cell:macrophage ratio, reduced frequency of buried fibrous caps (a surrogate marker of previous plaque disruption) and decreased incidence of calcification. Our data suggest that MMP-12 is critical for both plaque initiation and progression at multiple sites and that inhibition of MMP-12 activity using a selective compound exerts beneficial effects on atherosclerosis in the apoE knockout mouse model. Therefore utilisation of a MMP-12 specific inhibitor may prove useful for the treatment of progressive atherosclerosis.