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Cardiovascular Research 2006 71(3):586-595; doi:10.1016/j.cardiores.2006.05.009
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Copyright © 2006, European Society of Cardiology

Effect of broad-spectrum matrix metalloproteinase inhibition on atherosclerotic plaque stability

Jason L. Johnsona, Regina Fritsche-Danielsonb, Margareta Behrendtb, Annika Westin-Erikssonb, Håkan Wennbob, Margareta Herslofb, Marie Elebringb, Sarah J. Georgea, William L. McPheatb and Christopher L. Jacksona,*

aBristol Heart Institute, University of Bristol, Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom
bAstraZeneca R&D, Mölndal, Sweden

* Corresponding author. Tel./fax: +44 117 928 2534. Email address: chris.jackson{at}bristol.ac.uk

Objective: Matrix metalloproteinases (MMPs) form a large family of enzymes that collectively can degrade all components of the extracellular matrix, and there is widespread interest in developing MMP inhibitors for the prevention of atherosclerotic plaque rupture. We have therefore investigated the effects of a broad-spectrum MMP inhibitor, RS-130830, on plaque development and stability. This compound inhibits a wide range of MMPs at concentrations below 20 nmol/L.

Methods Apolipoprotein E knockout mice were fed a Western diet. Dietary administration of RS-130830 commenced at the same time as fat-feeding and continued for 8, 12, 26 or 36 weeks. To investigate the effect of RS-130830 on established plaques, mice were fed high-fat diet for 16 weeks before initiation of drug treatment and were terminated 20 weeks after this.

Results: Broad-spectrum MMP inhibition was associated with a significant increase in plaque area, but there was no change in the incidence of plaque rupture. There were unfavourable changes in phenotypic characteristics associated with plaque instability, such as an increased lipid content and decreased collagen content.

Conclusions: These data suggest that broad-spectrum MMP inhibition RS-130830 does not have a beneficial effect on atherosclerosis in the apolipoprotein E knockout mouse model, and indicate that more selective compounds would be preferable.

KEYWORDS Plaque rupture; Atherosclerosis; Matrix metalloproteinases; Animal models

Time for primary review 16 days


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