Proteinases and plaque rupture: unblocking the road to translation

Andrew C Newby

Research output: Contribution to journalArticle (Academic Journal)

24 Citations (Scopus)

Abstract

PURPOSE OF REVIEW: 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.

RECENT FINDINGS: 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.

SUMMARY: New opportunities exist to exploit proteinases as therapeutic targets in plaque rupture.

Original languageEnglish
Pages (from-to)358-66
Number of pages9
JournalCurrent Opinion in Lipidology
Volume25
Issue number5
DOIs
Publication statusPublished - Oct 2014

Keywords

  • ADAM Proteins
  • Amyloid Precursor Protein Secretases
  • Atherosclerosis
  • Cathepsin K
  • Genome-Wide Association Study
  • Humans
  • Macrophages
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinases
  • Membrane Proteins
  • Molecular Targeted Therapy
  • Myocardial Infarction
  • Plaque, Atherosclerotic

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