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Proteinases and plaque rupture: unblocking the road to translation
1University of Bristol and Bristol Heart Institute, Bristol, UK.
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.
Insights
Extracellular proteinases are key to plaque rupture, a cause of heart attacks. Research highlights promising therapeutic targets, including specific cathepsins and metalloproteinases, for future treatments.
Area of Science:
- Biochemistry
- Cardiovascular Research
- Pharmacology
Background:
- Atherosclerotic plaque rupture is the primary cause of myocardial infarctions.
- Extracellular proteinases play a critical role in the pathogenesis of plaque instability.
Purpose of the Study:
- To review recent advancements in understanding the role of extracellular proteinases in plaque rupture.
- To identify promising therapeutic targets for treating myocardial infarctions.
Main Methods:
- Literature review of studies published within the last five years.
- Analysis of the involvement of various proteinase families (cathepsins, serine proteinases, metalloproteinases) in atherogenesis.
Main Results:
- Cysteinyl cathepsins, particularly Cathepsin K, show potential as therapeutic targets due to their role in macrophage function and collagen degradation.
- A Disintegrin and Metalloproteinases (ADAMs) and ADAMs with Thrombospondin domains (ADAMTSs), such as ADAM-10, ADAM-17, and ADAMTS-7, are implicated in vascular remodeling and cardiovascular disease.
- Matrix metalloproteinases (MMPs), including MMP-12 and MMP-13, are identified as potential targets, with selective inhibitors available, and novel targets like MMP-8 and MMP-10 also being explored.
Conclusions:
- Significant progress has been made in linking specific extracellular proteinases to plaque rupture.
- New therapeutic strategies targeting these proteinases offer promising avenues for preventing myocardial infarctions.
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