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Proteinases and plaque rupture: unblocking the road to translation

Newby, Andrew C.

doi: 10.1097/MOL.0000000000000111
ATHEROSCLEROSIS: CELL BIOLOGY AND LIPOPROTEINS: Edited by Andrew Newby and Yury Miller
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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.

University of Bristol and Bristol Heart Institute, Bristol, UK

Correspondence to Prof Andrew C. Newby, Bristol Heart Institute, Research and Teaching Floor Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK. Tel: +44 1173423583; fax: +44 1179299737; e-mail: a.newby@bristol.ac.uk

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