title: A selective matrix metalloproteinase-12 inhibitor retards atherosclerotic plaque development in apolipoprotein E-knockout mice.
abstract: 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.
  
  
  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.
authors.affiliation: Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom. jason.l.johnson@bristol.ac.uk
authors.forename: Jason L
authors.initials: JL
authors.lastname: Johnson
authors.forename: Laurent
authors.initials: L
authors.lastname: Devel
authors.forename: Bertrand
authors.initials: B
authors.lastname: Czarny
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: George
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Jackson
authors.forename: Vassilis
authors.initials: V
authors.lastname: Rogakos
authors.forename: Fabrice
authors.initials: F
authors.lastname: Beau
authors.forename: Athanasios
authors.initials: A
authors.lastname: Yiotakis
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Newby
authors.forename: Vincent
authors.initials: V
authors.lastname: Dive
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D001835:Body Weight; D002114:Calcinosis / Q000201:enzymology / Q000517:prevention & control; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005355:Fibrosis; D015918:Infusion Pumps, Implantable; D055104:Infusions, Subcutaneous; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000172:deficiency / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009336:Necrosis; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D010641:Phenotype; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits
chemical_list: D001057:Apolipoproteins E; D008055:Lipids; D061965:Matrix Metalloproteinase Inhibitors; D010455:Peptides; D011480:Protease Inhibitors; C557203:RXP470.1 peptide; D053508:Matrix Metalloproteinase 12