The distal carboxyterminal domains of murine ADAMTS13 influence proteolysis of platelet‐decorated VWF strings in vivo

Maeyer, Bauke De; Meyer, Simon De; Feys, Hendrik B.; Pareyn, Inge; Vandeputte, Nele; Deckmyn, Hans; Vanhoorelbeke, Karen

doi:10.1111/j.1538-7836.2010.04008.x

Cited by 31 publications

(41 citation statements)

References 36 publications

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“…10 Reactions were performed in reaction buffer (50mM HEPES, 150mM NaCl, 5mM CaCl 2 , 1M ZnCl 2 , pH 7.4) using 6 L of plasma and a final concentration of 4M FRETS-VWF73 substrate (Peptides International). Fluorescence intensities were measured every 5 minutes for 1.5 hours with a Fluoroskan Ascent microplate fluorometer (Thermo Scientific) using excitation at 355 nm and emission at 460 nm at 37°C.…”

Section: Adamts13 Activity Assaymentioning

confidence: 99%

Protective anti-inflammatory effect of ADAMTS13 on myocardial ischemia/reperfusion injury in mice

Meyer

Savchenko

Haas

et al. 2012

Blood

109

123

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Coronary heart disease is a major cause of death in the western world. Although essential for successful recovery, reperfusion of ischemic myocardium is inevitably associated with reperfusion injury. To investigate a potential protective role of ADAMTS13, a protease cleaving von Willebrand factor multimers, during myocardial ischemia/reperfusion, we used a mouse model of acute myocardial infarction. We found that Adamts13 ؊/؊ mice developed larger myocardial infarctions than wild-type control mice, whereas treatment of wild-type mice with recombinant human ADAMTS13 (rhADAMTS13) led to smaller infarctions. The protective effect of ADAMTS13 was further confirmed by a significant reduction of cardiac troponin-I release and less myocardial apoptosis in mice that received rhADAMTS13 compared with controls. Platelets adherent to the blood vessel wall were observed in few areas in the heart samples from mice treated with vehicle and were not detected in samples from mice treated with rhADAMTS13. However, we observed a 9-fold reduction in number of neutrophils infiltrating ischemic myocardium in mice that were treated with rhADAMTS13, suggesting a potent anti-inflammatory effect of ADAMTS13 during heart injury. Our data show that ADAMTS13 reduces myocardial ischemia/reperfusion injury in mice and indicate that rhADAMTS13 could be of therapeutic value to limit myocardial ischemia/reperfusion injury. (Blood. 2012;120(26):5217-5223) IntroductionCoronary heart disease is the leading cause of death in the western world with approximately 1 million myocardial infarctions (MIs) each year just in the United States. 1,2 Acute myocardial infarction (AMI) is caused by thrombotic occlusion of a coronary artery. Although rapid restoration of the coronary circulation is critical for successful treatment, reperfusion itself exacerbates injury of previously ischemic myocardium. 1 The exact mechanisms of myocardial ischemia/reperfusion (MI/R) injury are not fully understood. 1 Given that cardiac ischemia is either unpredictable (MI) or inevitable (in patients undergoing cardioplegic arrest), there is great interest in developing strategies to minimize injury. von Willebrand factor (VWF) and its cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type-1 motif, member 13) play a pivotal role in platelet adhesion and thrombus formation. By specifically cleaving the VWF A2 domain, ADAMTS13 digests the most thrombogenic ultra-large VWF multimers (UL-VWF) into smaller, less hemostatically active VWF molecules. In addition, ADAMTS13's action on VWF downregulates inflammatory responses. As a result, using experimental mouse models, ADAMTS13 was shown to reduce both thrombosis and inflammation, including atherosclerosis. [3][4][5] An increasing amount of clinical evidence points to the possibility that VWF and ADAMTS13 are involved in MI pathogenesis. 6 To test this experimentally, we used a mouse model of acute myocardial infarction. Using mice deficient in ADAMTS13 and treating wild-type mice with human rhADAM...

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Section: Adamts13 Activity Assaymentioning

confidence: 99%

Protective anti-inflammatory effect of ADAMTS13 on myocardial ischemia/reperfusion injury in mice

Meyer

Savchenko

Haas

et al. 2012

Blood

109

123

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“…Endogenous platelets were labeled by intravenous administration of rhodamine 6G. 42 Microscopy was performed using a Nikon Eclipse TE200 inverted fluorescence microscope equipped with a 20ϫ PLAN objective (numeric aperture 0.4) coupled to an ORCA-R 2 Hamamatsu CCD camera. Images were recorded using Hokawo software (Hamamatsu Photonics).…”

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confidence: 99%

“…46,47 In vivo, it is debatable whether extraordinarily long VWF strings actually form either through self-association, or by association of plasma multimers with VWF strings, as the length of the strings visualized in vivo range from 20 to 100 m and VWF networks are not generally observed. 42,49 Which factors regulate platelet binding to VWF strings?A remarkable feature of VWF multimers anchored to endothelial cells is that they can rapidly recruit platelets from the circulation, This binding does not result in a rolling movement of the platelets but in a firm adhesion to VWF strings. Bound platelets become activated as evidenced by the presence of P-selectin and activated ␣IIb␤3 on their surface.…”

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confidence: 99%

“…58 In addition, although VWF strings can be generated in vitro over human endothelial cells under both venous and arterial flow conditions, 1,45 they are only observed in the venous vasculature in mice. 41,42,59 Whether this might be explained by the involvement of different attachment molecules in vitro and in vivo remains unclear. 45 It must also be considered that differences in VWF expression and WPB biology in arterial and venous endothelial cells could also play an important role.…”

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confidence: 99%

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Unwinding the von Willebrand factor strings puzzle

Ceunynck

Meyer

Vanhoorelbeke

2013

Blood

130

144

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Introductionvon Willebrand factor (VWF) strings correspond to ultra-large (UL) VWF multimers that, after secretion from the endothelium, remain anchored to the cell surface. As a result of this tethering and the rheologic forces of flow, these VWF multimers unravel, can bind platelets, and wave in the direction of the blood flow 1 (Figure 1). Since their discovery, platelet-decorated VWF strings have proved fascinating, and yet puzzling entities, with interesting and rather unique characteristics. VWF strings can be extraordinarily long, can be anchored to endothelial cells through a discrete number of attachment sites, contain active platelet binding sites, and are susceptible to specific proteolysis by its regulating protease, ADAMTS13 (a disintegrin-like and metalloprotease domain with thrombospondin type-1 motif, number 13). VWF strings are considered prothrombotic and might therefore contribute to the pathophysiology of thrombotic disorders, such as thrombotic thrombocytopenic purpura (TTP) and arterial thrombosis. In addition, platelet-decorated VWF strings can also provide a reactive surface for leukocytes and parasite-infected red blood cells, which has suggested possible roles in both inflammation and malaria.In this review, we discuss the typical features of these intriguing VWF strings and highlight questions that remain to be resolved and that would provide a better understanding of VWF string biochemistry. VWF strings were first discovered and studied in the absence of ADAMTS13, a situation that does not mimic normal physiologic conditions. In the majority of pathophysiologic conditions, plasma ADAMTS13 activity levels are at most decreased, but very rarely absent. To this end, a discussion on the possible involvement of VWF strings in disease pathology might serve to put VWF string research into perspective. VWF, UL-VWF multimers, and ADAMTS13VWF is the largest biopolymer present in plasma, and consists of multimers ranging in size from 500 to 10 000 kDa, with the largest multimers being the most hemostatically active. 2,3 The building block of these multimers is a mature VWF subunit consisting of D, A, B, C, and CK domains, 4,5 although the domain organization of VWF has recently been reannotated. 6 In circulation, VWF multimers adopt a folded, globular conformation that shields the platelet glycoprotein Ib (GPIb) binding sites in the VWF A1 domain. 7,8 This folding serves to prevent spontaneous binding of platelets to VWF in circulation. However, immobilization of VWF at sites of vascular injury (via the VWF A3-collagen interaction) leads to VWF unfolding in response to the shear forces exerted by the flowing blood. This exposes VWF A1 domains that, in turn, reveal the binding sites for the platelet GPIb receptor. The VWF-GPIb interaction is characterized by a fast association/dissociation rate, which enables platelets to "roll" over the VWF surface and provide the opportunity to establish firm platelet adhesion through the collagen receptors. [9][10][11][12] This adhesion step, which is partic...

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“…A recent study by de Maeyer et al reported platelet-UL-VWF string survival time over the activated endothelium of ϳ 5 seconds in Adamts13 ϩ/ϩ , whereas this was ϳ 13 seconds in Adamts13 Ϫ/Ϫ mice. 8 These results might suggest that even a small increase in lifetime of a platelet-UL-VWF string could potentially translate into a proinflammatory stimulus. Whether changes of platelet-UL-VWF string lifetime occur as a function of ADAMTS13 plasma concentration across the normal range in humans will be key to determining whether the proinflammatory effects of VWF strings are pertinent to the pathogenesis of human vascular diseases.…”

Section: Org Frommentioning

confidence: 99%