MMP‐13 binds to platelet receptors αIIbβ3 and GPVI and impairs aggregation and thrombus formation

Abstract

Essentials MMP‐13 has the potential to influence platelet function and thrombus formation directly.We sought to elucidate whether MMP‐13 is able to bind to specific platelet receptors.MMP‐13 is able to bind to platelet alphaIIbbeta3 (αIIbβ3) and glycoprotein (GP)VI.These interactions are sufficient to inhibit platelet aggregation and thrombus formation. BackgroundAcute thrombotic syndromes lead to atherosclerotic plaque rupture with subsequent thrombus formation, myocardial infarction and stroke. Following rupture, flowing blood is exposed to plaque components, including collagen, which triggers platelet activation and aggregation. However, plaque rupture releases other components into the surrounding vessel which have the potential to influence platelet function and thrombus formation.ObjectivesHere we sought to elucidate whether matrix metalloproteinase‐13 (MMP‐13), a collagenolytic metalloproteinase up‐regulated in atherothrombotic and inflammatory conditions, affects platelet aggregation and thrombus formation.ResultsWe demonstrate that MMP‐13 is able to bind to platelet receptors alphaIIbbeta3 (αIIbβ3) and platelet glycoprotein (GP)VI. The interactions between MMP‐13, GPVI and αIIbβ3 are sufficient to significantly inhibit washed platelet aggregation and decrease thrombus formation on fibrillar collagen.ConclusionsOur data demonstrate a role for MMP‐13 in the inhibition of both platelet aggregation and thrombus formation in whole flowing blood, and may provide new avenues of research into the mechanisms underlying the subtle role of MMP‐13 in atherothrombotic pathologies.

Release of Mitochondrial and Nuclear DNA During On-Pump Heart Surgery: Kinetics and Relation to Extracellular Vesicles

“…Interestingly, the targeted deletion of p66ShcA increased MMP-13 postinfarction. Unlike MMP-2 and MMP-9, MMP-13 is reported to reduce cardiac fibrosis (210) and thrombosis (210). MMP-13 is activated early and transitionally after myocardial infarction (211).…”

Matrix metalloproteinase‐13 unlucky for the forming thrombus

“…A number of the MMPs are noted to have catalytic activity at the platelet surface, and in the case of MMP‐2, intracellular cleavage of talin which may contribute to transmission of inside‐out signals leading to αIIbβ3 activation. Here, the mechanism of action of MMP‐13 on platelets did not seem to involve direct cleavage of GPVI or αIIbβ3. Whilst MMP‐13 could cleave recombinant purified forms of GPVI and αIIbβ3, as well as purified fibrinogen, treatment of platelets with MMP‐13 did not result in release of GPVI or αIIbβ3.…”

“…Matrix metalloproteinases (MMPs) are calcium‐dependent zinc‐containing endoproteases involved in extracellular matrix and non‐matrix protein degradation . In the latest issue of Research and Practice in Thrombosis and Haemostasis , Howes and colleagues investigated the role of MMP‐13 in platelet aggregation and thrombus formation and identified that MMP‐13 could engage important platelet receptors and influence platelet function in vitro. MMP‐13 is of great cardiovascular interest as expression of this metalloproteinase is significantly upregulated in a host of atherothrombotic and inflammatory conditions …”

“…In a series of adhesion assays using washed platelets and recombinant proteins, Howes and colleagues demonstrate that immobilized pro‐ or mature MMP‐13 is able to mediate static adhesion of platelets, and this adhesion could be disrupted by pretreatment of platelets with anti‐GPVI antibodies, or reagents that target the RGD‐binding site within integrin αIIbβ3. This suggests that adhesion of platelets to MMP‐13 involved both GPVI and αIIbβ3 receptors.…”

The Effect of Bay Leaf Extract (Syzygium polyanthum) on Reducing Overexpression of Matrix Metalloproteinases-13 in Acute Coronary Syndrome

“…Study by Huang et al, shows higher expression of MMP-9 in human compared to rats [22]. In vitro study by Howes et al shows MMP-13 role in platelet aggregation inhibition and thrombus formation [23]. This protease is upregulated in atherothrombotic and inflammatory conditions [24].…”