Comparison of the GPVI inhibitors losartan and honokiol

Onselaer, Marie-Blanche; Nagy, Magdolna; Pallini, C; Pike, Jeremy; Perrella, Gina; Quintanilla, Lourdes Garcia; Eble, Johannes A.; Poulter, Natalie S.; Heemskerk, Johan W. M.; Watson, Steve P.

doi:10.1080/09537104.2019.1585526

Cited by 24 publications

(24 citation statements)

References 38 publications

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“…Moreover. losartan, a recently characterized GPVI inhibitor that at low doses does not cross‐react with FcɣRIIA, 29 has minimal or negligible effects on platelet aggregation induced by fibrillar Aβ peptides (Figure S1). These results indicate that amyloid peptides activate platelets through the GPIb‐IX‐V/FcγRIIA axis.…”

Section: Resultsmentioning

confidence: 99%

Fibrillar amyloid peptides promote platelet aggregation through the coordinated action of ITAM‐ and ROS‐dependent pathways

Visconte

Canino

Vismara

et al. 2020

Journal of Thrombosis and Haemostasis

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Background: Amyloid peptides Aβ40 and Aβ42, whose deposition in brain correlates with Alzheimer disease, are also present in platelets and have prothrombotic activities. Objective: In this study, we analyze the ability of Aβ peptides to form fibrils and to induce platelet activation and aggregation. Methods: Aβ40, Aβ42, and their scrambled peptides were diluted in phosphate buffered saline and fibrillogenesis was investigated by ThioflavinT and Congo Red. Aggregation, protein phosphorylation, and reactive oxygen species (ROS) production were analyzed. Results: Aβ40 and Aβ42, but not scrambled peptides, were able to form fibrils when diluted in phosphate buffered saline. Fibrillogenesis of Aβ42 was very rapid, whereas fibril formation by Aβ40 was completed only after 48 hours of incubation. Fibrillar Aβ40 and Aβ42 promoted dose-dependent aggregation of washed platelets in the presence of extracellular CaCl 2. Cleavage of GPIbα by mocarhagin or blockade of the ITAM-containing FcγRIIA prevented platelet aggregation induced by fibrillary Aβ40 and Aβ42. Fibrillar Aβ peptides stimulated the phosphorylation of FcγRIIA, resulting in the downstream stimulation of PLC, protein kinase C, and phosphoinositide 3-kinases, whose activity was necessary for full aggregation of platelets. Fibrillar Aβ peptides also induced ROS generation, and NOX inhibitors, as well as ROS scavengers, prevented platelet aggregation. However, Aβ peptide-induced ROS production did not require binding to GPIbα or activation of FcγRIIA, but was initiated by CD36, which provided an important contribution to full platelet aggregation. Conclusion: These results suggest that fibrillar amyloid Aβ40 and Aβ42 induce platelet aggregation through the recruitment of GPIb-IX-V and CD36, which requires the convergence of ITAM-and ROS-dependent pathways.

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Section: Resultsmentioning

confidence: 99%

Fibrillar amyloid peptides promote platelet aggregation through the coordinated action of ITAM‐ and ROS‐dependent pathways

Visconte

Canino

Vismara

et al. 2020

Journal of Thrombosis and Haemostasis

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“…GPVI induced release of fibrinogen accounted for amyloid aggregate formation in vitro. In vivo, enhanced platelet accumulation at injured vessels after stimulation of platelets with Aβ40 was markedly reduced when we injected GPVI deficient platelets or treated platelets with losartan, a small molecule which has been described to inhibit collagen-induced platelet aggregation in mice (23,24), inhibited Aβ40-induced platelet aggregation and ATP and fibrinogen release but had no effect on platelet-mediated amyloid aggregate formation. These results are in line with studies showing that the use of angiotensin receptor blockers, such as losartan, restore cerebrovascular dysfunction but have no effects on memory decline or AD pathology (as in, specifically, amyloidosis) (32,33).…”

Section: Discussionmentioning

confidence: 98%

The collagen receptor glycoprotein VI promotes platelet-mediated aggregation of β-amyloid

et al. 2020

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Cerebral amyloid angiopathy (CAA) and β-amyloid (Aβ) deposition in the brain parenchyma are hallmarks of Alzheimer’s disease (AD). We previously reported that platelets contribute to Aβ aggregation in cerebral vessels by secreting the factor clusterin upon binding of Aβ40 to the fibrinogen receptor integrin αIIbβ3. Here, we investigated the contribution of the collagen receptor GPVI (glycoprotein VI) in platelet-induced amyloid aggregation. Using platelets isolated from GPVI–wild type and GPVI-deficient human donors and mice, we found that Aβ40 bound to GPVI, which induced the release of ATP and fibrinogen, resulting in platelet aggregation. Binding of Aβ40 to integrin αIIbβ3, fibrinogen, and GPVI collectively contributed to the formation of amyloid clusters at the platelet surface. Consequently, blockade of αIIbβ3 or genetic loss of GPVI reduced amyloid fibril formation in cultured platelets and decreased the adhesion of Aβ-activated platelets to injured carotid arteries in mice. Application of losartan to inhibit collagen binding to GPVI resulted in decreased Aβ40-stimulated platelet activation, factor secretion, and platelet aggregation. Furthermore, the application of GPVI- or integrin-blocking antibodies reduced the formation of platelet-associated amyloid aggregates. Our findings indicate that Aβ40 promotes platelet-mediated amyloid aggregation by binding to both GPVI and integrin αIIbβ3. Blocking these pathways may therapeutically reduce amyloid plaque formation in cerebral vessels and the brain parenchyma of patients.

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“…Platelet activation was terminated with a sodium dodecyl sulphate (SDS) reducing sample buffer. Whole cell lysates (WCL) were prepared and immunoblotted as previously described [ 14 ]. Syk and PLCγ2 were immunoprecipitated as previously described [ 14 ].…”

Section: Methodsmentioning

confidence: 99%

“…Whole cell lysates (WCL) were prepared and immunoblotted as previously described [ 14 ]. Syk and PLCγ2 were immunoprecipitated as previously described [ 14 ].…”

Section: Methodsmentioning

confidence: 99%

Role of Tyrosine Kinase Syk in Thrombus Stabilisation at High Shear

Perrella

Montague

Brown

et al. 2022

IJMS

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Understanding the pathways involved in the formation and stability of the core and shell regions of a platelet-rich arterial thrombus may result in new ways to treat arterial thrombosis. The distinguishing feature between these two regions is the absence of fibrin in the shell which indicates that in vitro flow-based assays over thrombogenic surfaces, in the absence of coagulation, can be used to resemble this region. In this study, we have investigated the contribution of Syk tyrosine kinase in the stability of platelet aggregates (or thrombi) formed on collagen or atherosclerotic plaque homogenate at arterial shear (1000 s−1). We show that post-perfusion of the Syk inhibitor PRT-060318 over preformed thrombi on both surfaces enhances thrombus breakdown and platelet detachment. The resulting loss of thrombus stability led to a reduction in thrombus contractile score which could be detected as early as 3 min after perfusion of the Syk inhibitor. A similar loss of thrombus stability was observed with ticagrelor and indomethacin, inhibitors of platelet adenosine diphosphate (ADP) receptor and thromboxane A2 (TxA2), respectively, and in the presence of the Src inhibitor, dasatinib. In contrast, the Btk inhibitor, ibrutinib, causes only a minor decrease in thrombus contractile score. Weak thrombus breakdown is also seen with the blocking GPVI nanobody, Nb21, which indicates, at best, a minor contribution of collagen to the stability of the platelet aggregate. These results show that Syk regulates thrombus stability in the absence of fibrin in human platelets under flow and provide evidence that this involves pathways additional to activation of GPVI by collagen.

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Comparison of the GPVI inhibitors losartan and honokiol

Cited by 24 publications

References 38 publications

Fibrillar amyloid peptides promote platelet aggregation through the coordinated action of ITAM‐ and ROS‐dependent pathways

Fibrillar amyloid peptides promote platelet aggregation through the coordinated action of ITAM‐ and ROS‐dependent pathways

The collagen receptor glycoprotein VI promotes platelet-mediated aggregation of β-amyloid

Role of Tyrosine Kinase Syk in Thrombus Stabilisation at High Shear

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