Effect of broad-spectrum matrix metalloproteinase inhibition on atherosclerotic plaque stability.
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.
Johnson
Jason L
JL
Bristol Heart Institute, University of Bristol, Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom.
Fritsche-Danielson
Regina
R
Behrendt
Margareta
M
Westin-Eriksson
Annika
A
Wennbo
Håkan
H
Herslof
Margareta
M
Elebring
Marie
M
George
Sarah J
SJ
McPheat
William L
WL
Jackson
Christopher L
CL
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016122:Brachiocephalic Trunk / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000627:therapeutic use* / Q000633:toxicity; D005260:Female; D006877:Hydroxamic Acids / Q000627:therapeutic use* / Q000633:toxicity; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000097:blood; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D018345:Mice, Knockout; D012422:Rupture, Spontaneous / Q000517:prevention & control; D016019:Survival Analysis
D001057:Apolipoproteins E; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D008055:Lipids; D061965:Matrix Metalloproteinase Inhibitors; C513962:RS-130830; D003094:Collagen