title: Proteinases and plaque rupture: unblocking the road to translation.
abstract: OBJECTIVE
  To review progress over the past 5 years in relating extracellular proteinases to plaque rupture, the cause of most myocardial infarctions, and consider the most promising prospects for developing related treatments.
  
  
  RESULTS
  Cysteinyl cathepsins have been implicated in multiple macrophage functions that could promote plaque rupture. Cathepsin K is an attractive target because it is a collagenase and selective inhibitors are already being used in phase III clinical trials. Several serine proteinases clearly influence vascular remodelling and atherogenesis but important, unrelated actions limit their value as therapeutic targets. Among the metalloproteinases, new evidence supports roles for A Disintigrin and Metalloproteinases (ADAMs), including ADAM-10, ADAM-17 and ADAM-33, which suggest that selective inhibitors might be effective treatments. For ADAMs with ThromboSpondin domains (ADAMTSs), there are biological and genome-wide association data linking ADAMTS-7 to incidence of coronary heart disease but not increased risk of myocardial infarctions. In the case of matrix metalloproteinases (MMPs), selective inhibitors of MMP-12 and MMP-13 are available and may be appropriate for development as therapies. Novel targets, including MMP-8, MMP-10, MMP-14, MMP-19, MMP-25 and MMP-28, are also being considered.
  
  
  CONCLUSIONS
  New opportunities exist to exploit proteinases as therapeutic targets in plaque rupture.
authors.affiliation: University of Bristol and Bristol Heart Institute, Bristol, UK.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Newby
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D056657:Cathepsin K / Q000037:antagonists & inhibitors / Q000378:metabolism; D055106:Genome-Wide Association Study; D006801:Humans; D008264:Macrophages / Q000201:enzymology / Q000473:pathology; D061965:Matrix Metalloproteinase Inhibitors / Q000378:metabolism / Q000627:therapeutic use; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009203:Myocardial Infarction / Q000201:enzymology / Q000209:etiology / Q000473:pathology*; D058226:Plaque, Atherosclerotic / Q000201:enzymology* / Q000473:pathology
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; D053829:Amyloid Precursor Protein Secretases; D056657:Cathepsin K; D051722:ADAM Proteins; C450441:ADAM33 protein, human; D020782:Matrix Metalloproteinases; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human