Key result
Broad-spectrum MMP inhibition increases plaque area and worsens phenotype without altering rupture in ApoE mice.
Why the study?
Does broad-spectrum MMP inhibition with RS-130830 improve atherosclerotic plaque stability in apolipoprotein E knockout mice?
Does broad-spectrum MMP inhibition with RS-130830 improve atherosclerotic plaque stability in apolipoprotein E knockout mice?
Broad-spectrum MMP inhibition with RS-130830 worsened atherosclerotic plaque characteristics in ApoE knockout mice, suggesting that more selective MMP inhibitors are needed.
May discourage broad MMP inhibition in atherosclerosis; leaves open selective targeting in human plaque studies.
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.
No takes yet. Share an insight, caveat, or question.
Johnson et al. (2006) studied Atherosclerosis. RS-130830 was evaluated on Plaque area and incidence of plaque rupture. Broad-spectrum MMP inhibition with RS-130830 significantly increased plaque area and caused unfavorable phenotypic changes without altering plaque rupture incidence in ApoE knockout mice.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: