scholarly journals Amyloid β protein negatively regulates the human platelet activation induced by thrombin receptor-activating protein

2021 ◽  
Author(s):  
Daisuke Mizutani ◽  
Haruhiko Tokuda ◽  
Takashi Onuma ◽  
Kodai Uematsu ◽  
Daiki Nakashima ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Intracerebral Hemorrhage ◽  
Platelet Activation ◽  
Human Platelet ◽  
Amyloid Β ◽  
Human Platelets ◽  
The Other ◽  
Thrombin Receptor ◽  
Amyloid Β Protein ◽  
Β Protein

Abstract Background: Amyloid β protein (Aβ) is the main product derived from amyloid precursor protein (APP) by sequential enzymatic actions. Deposition of Aβ in the brain parenchyma or cerebral vessels is a primary morphological feature of Alzheimer’s disease (AD). In addition, abnormal accumulation of Aβ in the cerebral vessels is known as cerebral amyloid angiopathy (CAA), which is considered a risk factor for intracerebral hemorrhage, particularly in the elderly. CAA reportedly contributes to the development of vascular cognitive decline in addition to AD. On the other hand, human platelets are recognized as the principal components affecting the onset and progression of AD. Although there are several studies showing that Aβ directly modulates human platelet functions, the exact mechanism underlying the Aβ effects on human platelets remains to be elucidated.Methods: The present study investigated the effects of Aβ on human platelet activation using a platelet aggregometer with laser scattering, followed by western blot analysis and ELISA.Results: Aβ at doses up to 7 µM alone failed to affect platelet aggregation or platelet-derived growth factor (PDGF)-AB secretion. On the other hand, Aβ decreased the platelet aggregation induced by thrombin receptor-activating protein (TRAP), but not collagen or ADP. Aβ also suppressed platelet aggregation induced by SCP0237, a selective protease-activated receptor (PAR)-1 agonist, and A3227, a selective PAR-4 agonist. The PDGF-AB secretion and the phosphorylated-heat shock protein (HSP)27 release by TRAP were inhibited by Aβ. In addition, the TRAP-induced phosphorylation of JNK and the phosphorylation of p38 MAP kinase followed by phosphorylation of HSP27 were reduced by Aβ.Conclusion: The results of the present study strongly suggest that Aβ negatively regulates PAR-elicited human platelet activation. These findings may indicate one of the causes of intracerebral hemorrhage due to CAA.

scholarly journals Amyloid β protein negatively regulates human platelet activation induced by thrombin receptor-activating protein

2021 ◽  
Author(s):  
Daisuke Mizutani ◽  
Haruhiko Tokuda ◽  
Takashi Onuma ◽  
Kodai Uematsu ◽  
Daiki Nakashima ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Intracerebral Hemorrhage ◽  
Platelet Activation ◽  
Human Platelet ◽  
Amyloid Β ◽  
P38 Map Kinase ◽  
Thrombin Receptor ◽  
Amyloid Β Protein ◽  
Laser Scattering ◽  
Β Protein

Abstract Amyloid β protein deposition in cerebral vessels, a characteristic of Alzheimer's disease, is a risk factor for intracerebral hemorrhage. Amyloid β protein directly modulates human platelet function; however, the exact mechanism of action is unclear. Therefore, we investigated the effects of amyloid β protein on human platelet activation using an aggregometer with laser scattering. Amyloid β protein decreased platelet aggregation induced by thrombin receptor-activating protein, but not by collagen and ADP. Amyloid β protein also suppressed platelet aggregation induced by SCP0237 and A3227. Platelet-derived growth factor-AB secretion and phosphorylated-heat shock protein 27 release by thrombin receptor-activating protein were inhibited by amyloid β protein. Additionally, thrombin receptor-activating protein-induced phosphorylation of JNK and p38 MAP kinase was reduced by amyloid β protein. Collectively, our results strongly suggest that amyloid β protein negatively regulates protease-activated receptor-elicited human platelet activation. These findings may indicate a cause of intracerebral hemorrhage due to amyloid β protein.

scholarly journals Ca2+-mobilizing actions of amyloid β-protein in human platelets.

1996 ◽  
Vol 71 ◽  
pp. 73
Author(s):  
Haruo Takemura ◽  
Hiroki Ishikawa ◽  
Hiroki Ozawa ◽  
Toshikazu Saito ◽  
Naohiko Takahata ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Human Platelets ◽  
Amyloid Β Protein ◽  
Β Protein

scholarly journals Human platelet aggregation by murine monoclonal antiplatelet antibodies is subtype-dependent

Blood ◽  
1993 ◽  
Vol 81 (7) ◽  
pp. 1792-1800 ◽  
Author(s):  
S De Reys ◽  
C Blom ◽  
B Lepoudre ◽  
PJ Declerck ◽  
M De Ley ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Platelet Aggregation ◽  
Platelet Activation ◽  
Human Platelet ◽  
Human Platelets ◽  
Antigen Recognition ◽  
Metabolic Inhibitors ◽  
Antigen Binding ◽  
Human Platelet Aggregation ◽  
Murine Monoclonal Antibodies

Abstract Twenty murine monoclonal antibodies (MoAbs) generated against different human platelet antigens induced clumping of human platelets in plasma and buffer. Whereas one MoAb could agglutinate platelets, clumping for 19 MoAbs was blocked by metabolic inhibitors, indicating that these induce platelet activation. Fifteen MoAbs were of IgG1, two of IgG2a, and two of IgG2b subtype. F(ab')2 fragments of these did not evoke an aggregatory response, but specifically inhibited aggregations by and binding of their respective intact MoAbs to platelets. Single-platelet counting technology indicated that the MoAbs bind through their antigen- binding and Fc domains mainly to the surface of the same platelet, rather than cause interplatelet-binding. Despite these similarities, the mechanism of action was nevertheless subtype-dependent. Aggregation induced by all IgG1 antibodies could consistently be prevented by blocking the Fc gamma II-receptor, whereas aggregations induced by all IgG2 antibodies still occurred with blocked Fc-receptor, provided functional complement was present. We therefore conclude that platelet activation by MoAb-binding is initiated by antigen recognition followed by an Fc domain-dependent step, which involves the Fc gamma II-receptor for IgG1-type MoAbs and complement-binding for IgG2-type MoAbs. Thus, antibodies of different subtypes can aggregate platelets via different pathways.

scholarly journals Human platelet aggregation by murine monoclonal antiplatelet antibodies is subtype-dependent

Blood ◽  
1993 ◽  
Vol 81 (7) ◽  
pp. 1792-1800 ◽  
Author(s):  
S De Reys ◽  
C Blom ◽  
B Lepoudre ◽  
PJ Declerck ◽  
M De Ley ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Platelet Aggregation ◽  
Platelet Activation ◽  
Human Platelet ◽  
Human Platelets ◽  
Antigen Recognition ◽  
Metabolic Inhibitors ◽  
Antigen Binding ◽  
Human Platelet Aggregation ◽  
Murine Monoclonal Antibodies

Twenty murine monoclonal antibodies (MoAbs) generated against different human platelet antigens induced clumping of human platelets in plasma and buffer. Whereas one MoAb could agglutinate platelets, clumping for 19 MoAbs was blocked by metabolic inhibitors, indicating that these induce platelet activation. Fifteen MoAbs were of IgG1, two of IgG2a, and two of IgG2b subtype. F(ab')2 fragments of these did not evoke an aggregatory response, but specifically inhibited aggregations by and binding of their respective intact MoAbs to platelets. Single-platelet counting technology indicated that the MoAbs bind through their antigen- binding and Fc domains mainly to the surface of the same platelet, rather than cause interplatelet-binding. Despite these similarities, the mechanism of action was nevertheless subtype-dependent. Aggregation induced by all IgG1 antibodies could consistently be prevented by blocking the Fc gamma II-receptor, whereas aggregations induced by all IgG2 antibodies still occurred with blocked Fc-receptor, provided functional complement was present. We therefore conclude that platelet activation by MoAb-binding is initiated by antigen recognition followed by an Fc domain-dependent step, which involves the Fc gamma II-receptor for IgG1-type MoAbs and complement-binding for IgG2-type MoAbs. Thus, antibodies of different subtypes can aggregate platelets via different pathways.

Protease-activated receptors 1 and 4 do not stimulate Gi signaling pathways in the absence of secreted ADP and cause human platelet aggregation independently of Gisignaling

Blood ◽  
2002 ◽  
Vol 99 (10) ◽  
pp. 3629-3636 ◽  
Author(s):  
Soochong Kim ◽  
Carolyn Foster ◽  
Anna Lecchi ◽  
Todd M. Quinton ◽  
Dina M. Prosser ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Adenylyl Cyclase ◽  
Signaling Pathways ◽  
Human Platelet ◽  
Adenosine Diphosphate ◽  
Human Platelets ◽  
P2y12 Receptor ◽  
General Mechanism ◽  
Thrombin Receptor ◽  
Human Platelet Aggregation

Thrombin is an important agonist for platelet activation and plays a major role in hemostasis and thrombosis. Thrombin activates platelets mainly through protease-activated receptor 1 (PAR1), PAR4, and glycoprotein Ib. Because adenosine diphosphate and thromboxane A2 have been shown to cause platelet aggregation by concomitant signaling through Gq and Gipathways, we investigated whether coactivation of Gq and Gi signaling pathways is the general mechanism by which PAR1 and PAR4 agonists also activate platelet fibrinogen receptor (αIIbβ3).  A PAR1-activating peptide, SFLLRN, and PAR4-activating peptides GYPGKF and AYPGKF, caused inhibition of stimulated adenylyl cyclase in human platelets but not in the presence of either Ro 31-8220, a protein kinase C selective inhibitor that abolishes secretion, or AR-C66096, a P2Y12 receptor–selective antagonist; α-thrombin–induced inhibition of adenylyl cyclase was also blocked by Ro 31-8220 or AR-C66096. In platelets from a P2Y12 receptor–defective patient, α-thrombin, SFLLRN, and GYPGKF also failed to inhibit adenylyl cyclase. In platelets from mice lacking the P2Y12 receptor, neither α-thrombin nor AYPGKF caused inhibition of adenylyl cyclase. Furthermore, AR-C66096 caused a rightward shift of human platelet aggregation induced by the lower concentrations of α-thrombin and AYPGKF but had no effect at higher concentrations. Similar results were obtained with platelets from mice deficient in the P2Y12. We conclude that (1)thrombin- and thrombin receptor-activating peptide–induced inhibition of adenylyl cyclase in platelets depends exclusively on secreted adenosine diphosphate that stimulates Gi signaling pathways and (2) thrombin and thrombin receptor-activating peptides cause platelet aggregation independently of Gi signaling.

Effect of parathyroid-hormone-related protein on human platelet activation

2007 ◽  
Vol 113 (7) ◽  
pp. 319-327 ◽  
Author(s):  
Arantxa Ortega ◽  
Ma Teresa Pérez de Prada ◽  
Petra J. Mateos-Cáceres ◽  
Priscila Ramos Mozo ◽  
Juan J. González-Armengol ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Platelet Aggregation ◽  
Protein Kinase ◽  
Western Blot ◽  
Platelet Activation ◽  
Human Platelet ◽  
Human Platelets ◽  
Related Protein ◽  
Induce Platelet Aggregation ◽  
Parathyroid Hormone Related Protein

Evidence suggests that PTHrP [PTH (parathyroid hormone)-related protein] can act as an inflammatory mediator in several pathological settings including cardiovascular disease. The aim of the present study was to determine whether PTHrP might be involved in human platelet activation. We used a turbidimetric method to determine platelet aggregation. The expression of PTH1R (PTH type 1 receptor) in human platelets was analysed by Western blot and flow cytometry analyses. PTHrP-(1–36) (10−7 mol/l) by itself failed to modify the activation of platelets. However, it significantly enhanced ADP-induced platelet activation, and also increased the ability of other agonists (thrombin, collagen and arachidonic acid) to induce platelet aggregation. H89 (10−6 mol/l) and 25×10−6 mol/l Rp-cAMPS (adenosine 3′,5′-cyclic monophosphorothioate Rp-isomer), two protein kinase A inhibitors, and 25×10−9 mol/l bisindolylmaleimide I, a protein kinase C inhibitor, partially decreased the enhancing effect of PTHrP-(1–36) on ADP-induced platelet activation. Meanwhile, 10−6 mol/l PTHrP-(7–34), a PTH1R antagonist, as well as 10−5 mol/l PD098059, a MAPK (mitogen-activated protein kinase) inhibitor, or a farnesyltransferase inhibitor abolished this effect of PTHrP-(1–36). Moreover, 10−7 mol/l PTHrP-(1–36) increased (2-fold over control) MAPK activation in human platelets. PTH1R was detected in platelets, and the number of platelets expressing it on their surface in patients during AMI (acute myocardial infarction) was not different from that in a group of patients with similar cardiovascular risk factors without AMI. Western blot analysis showed that total PTH1R protein levels were markedly higher in platelets from control than those from AMI patients. PTH1R was found in plasma, where its levels were increased in AMI patients compared with controls. In conclusion, human platelets express the PTH1R. PTHrP can interact with this receptor to enhance human platelet activation induced by several agonists through a MAPK-dependent mechanism.

scholarly journals Human platelet activation by C3a and C3a des-arg.

1983 ◽  
Vol 158 (2) ◽  
pp. 603-615 ◽  
Author(s):  
M J Polley ◽  
R L Nachman
Keyword(s):  
Platelet Aggregation ◽  
Analysis Of Variance ◽  
Platelet Activation ◽  
Human Platelet ◽  
Human Platelets ◽  
Serotonin Release ◽  
Release Reaction ◽  
C Terminus ◽  
Induced Aggregation ◽  
Synergistic Reaction

C3a liberated from C3 by treatment with C3 convertase (or by trypsin) induced aggregation of gel-filtered human platelets and stimulated serotonin release. At concentrations of 10(-10) M to 8 X 10(-12) M, C3a induced aggregation when added alone to platelets. However, at lower concentrations (2 X 10(-12) M) C3a did not aggregate platelets directly but exhibited highly significant synergism (two-way analysis of variance P less than 0.0001) with ADP in mediating platelet aggregation and release of serotonin. Removal of the C-terminus arginine from C3a abolished anaphylotoxin activity but did not affect the platelet-stimulating activity of the peptide. C3a and C3a des-arg were equally reactive in mediating platelet aggregation and release of serotonin. Further C3a and C3a des-arg exhibited synergism with ADP of equal significance in both aggregation and the release reaction. The concentrations of C3a required for the platelet-stimulating activity involve relatively small number of molecules per platelet (4,000-10,000 for the synergistic reaction with ADP). These data suggest the possibility of a C3a (C3a des-arg) receptor on human platelets. This premise is strengthened by the demonstration ultrastructurally of C3a on the platelet membrane subsequent to C3a stimulation.

Calcium mobilization evoked by amyloid β-protein involves inositol 1,4,5-trisphosphate production in human platelets

Life Sciences ◽  
1998 ◽  
Vol 62 (8) ◽  
pp. 705-713 ◽  
Author(s):  
Hiroki Ishikawa ◽  
Hiroki Ozawa ◽  
Toshikazu Saito ◽  
Naohiko Takahata ◽  
Haruo Takemura
Keyword(s):  
Amyloid Β ◽  
Human Platelets ◽  
Calcium Mobilization ◽  
Amyloid Β Protein ◽  
Β Protein ◽  
Inositol 1,4,5 Trisphosphate

Ticlopidine Facilitates the Deaggregation of Human Platelets Aggregated by Thrombin

1994 ◽  
Vol 71 (01) ◽  
pp. 091-094 ◽  
Author(s):  
M Cattaneo ◽  
B Akkawat ◽  
R L Kinlough-Rathbone ◽  
M A Packham ◽  
C Cimminiello ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Platelet Aggregation ◽  
Prostaglandin E1 ◽  
Human Platelet ◽  
Adenosine Diphosphate ◽  
Human Platelets ◽  
Before And After ◽  
Normal Human ◽  
Platelet Aggregates ◽  
Induced Aggregation

SummaryNormal human platelets aggregated by thrombin undergo the release reaction and are not readily deaggregated by the combination of inhibitors hirudin, prostaglandin E1 (PGE1) and chymotrypsin. Released adenosine diphosphate (ADP) plays an important role in the stabilization of thrombin-induced human platelet aggregates. Since ticlopidine inhibits the platelet responses to ADP, we studied thrombin-induced aggregation and deaggregation of 14C-serotonin-labeled platelets from 12 patients with cardiovascular disease before and 7 days after the oral administration of ticlopidine, 250 mg b.i.d. Before and after ticlopidine, platelets stimulated with 1 U/ml thrombin aggregated, released about 80–90% 14C-serotinin and did not deaggregate spontaneously within 5 min from stimulation. Before ticlopidine, hirudin (5× the activity of thrombin) and PGE1 (10 μmol/1) plus chymotrypsin (10 U/ml) or plasmin (0.06 U/ml), added at the peak of platelet aggregation, caused slight or no platelet deaggregation. After ticlopidine, the extent of platelet deaggregation caused by the same inhibitors was significantly greater than before ticlopidine. The addition of ADP (10 μmol/1) to platelet suspensions 5 s after thrombin did not prevent the deaggregation of ticlopidine-treated platelets. Thus, ticlopidine facilitates the deaggregation of thrombin-induced human platelet aggregates, most probably because it inhibits the effects of ADP on platelets.

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