A molecular signaling model of platelet phosphoinositide and calcium regulation during homeostasis and P2Y1 activation

Purvis, Jeremy E.; Chatterjee, Manash; Brass, Lawrence F.; Diamond, Scott L.

doi:10.1182/blood-2008-05-157883

Cited by 75 publications

(96 citation statements)

References 51 publications

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“…20 Because platelets produce interrelated responses to combinations of signaling cues simultaneously and this is central to evaluating patient-specific clinical status, developing predictive models capable of simulating cellular response to multiple stimuli is critical. Given the complexity of an ODE model to simulate the behavior of platelets in response to a single activator (eg, modeling ADP activation used 77 reactions 7 ), Chatterjee et al used machine training of neural networks to predict the response of platelets to multiple activators. 21 Neural networks are efficient in learning patterns of input and predicting outputs by altering the strength (weights) of connections in the network.…”

Section: Platelet Activation Modelsmentioning

confidence: 99%

“…The model correctly predicted that there was a TF concentration threshold required to activate the coagulation system to generate the thrombin required for a hemostatic response. In addition, the computational model introduced by Purvis et al 7 to simulate ADP-mediated platelet activation provided insight into possible mechanisms of negativefeedback signaling and cell-to-cell variation across platelet populations. Furthermore, the kinetic model of fibrin polymerization introduced by Weisel and Nagaswami 8 revealed that changes in the rate of fibrinopeptide cleavage were sufficient to explain many nonintuitive experimental observations regarding the effects of ionic strength or reduction of fibrinopeptide B levels on fibrin polymerization.…”

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confidence: 99%

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Computational Approaches to Studying Thrombus Development

Kamocka

Alber

et al. 2011

ATVB

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Abstract-In addition to descriptive biological models, many computational models have been developed for hemostasis/ thrombosis that provide quantitative characterization of thrombus development. Simulations using computational models that have been developed for coagulation reactions, platelet activation, and fibrinogen assembly have been shown to be in close agreement with experimental data. Models of processes involved in hemostasis/thrombosis are being integrated to simulate the development of the thrombus simultaneously in time and space. Key Words: blood coagulation Ⅲ blood flow Ⅲ coagulation Ⅲ platelets Ⅲ thrombosis Ⅲ computational model Ⅲ stochastic multiscale model Ⅲ thrombus development S ignificant progress has been made in our understanding of the hemostatic response. For instance, coagulation pathways 1 have been developed that describe the interactions among different elements and provide insight into the regulation of the response. Similarly, advances in platelet biology 2 have elucidated pathways of platelet activation and identified and characterized molecular components involved in intracellular signaling, as well as surface proteins mediating adhesion to the damaged vessel wall, to other platelets, and to other thrombus components. Furthermore, the development of transgenic, 3,4 gene knockout, and gene knock-in technologies has enabled exploration of the physiological roles of individual components in vivo using sophisticated hemostatic experimental systems. More recently, genomic and proteomic approaches have identified new elements modifying the hemostatic response.The initial identification of hemostatic components and description of coagulation or platelet signaling pathways were qualitative, 4,5 describing the order of interaction among components in coagulation or platelet behavior. These biological and biochemical models were extremely valuable, suggesting how these processes might be regulated and providing an understanding of how deficiencies or dysregulation of particular components leads to pathological states.In addition to these descriptive biological models, computational models have been developed for hemostatic processes that provide quantitative characterization of thrombus development. For instance, the tissue factor (TF)-initiated coagulation model introduced by Hockin et al 6 presented a quantitative description of the network of coagulation reactions. The model correctly predicted that there was a TF concentration threshold required to activate the coagulation system to generate the thrombin required for a hemostatic response. In addition, the computational model introduced by Purvis et al 7 to simulate ADP-mediated platelet activation provided insight into possible mechanisms of negativefeedback signaling and cell-to-cell variation across platelet populations. Furthermore, the kinetic model of fibrin polymerization introduced by Weisel and Nagaswami 8 revealed that changes in the rate of fibrinopeptide cleavage were sufficient to explain many nonintuitive experimental obs...

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Section: Platelet Activation Modelsmentioning

confidence: 99%

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confidence: 99%

Computational Approaches to Studying Thrombus Development

Kamocka

Alber

et al. 2011

ATVB

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“…Stochastic simulations were used to describe platelet homeostasis and activation via P 2 Y 1 receptor [18]; a mathematical model of PAR 1 -mediated platelet activation was also developed [19]. Recently, we expanded these modeling approaches to include all intracellular compartments, describe calcium oscillations and procoagulant platelets formation as a result of mitochondrial collapse [20].…”

Section: Introductionmentioning

confidence: 99%

Modulation and pre-amplification of PAR1 signaling by ADP acting via the P2Y12 receptor during platelet subpopulation formation

Шахиджанов

Shaturny

Panteleev

et al. 2015

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…Platelets and MKs both exhibit ionic currents and changes in shape and adhesiveness after being activated by ADP, ATP, thromboxane, collagen, thrombin, and fibrinogen via increases in cytosolic Ca 2ϩ concentration ([Ca 2ϩ ] i ) (19, 23-25, 32, 33, 52). Several sources and mediators have been identified in Ca 2ϩ signaling in platelets (24,31,43,44). Summarizing the results of multiple studies, the compartmentalized model of [Ca 2ϩ ] i regulation pathways in platelets and MKs consists of a G protein-mediated, protein kinase C (PKC) regulation by phospholipase C␤ (PLC␤) followed by calcium release (stored in the dense tubular system) activating the phosphoinositide (PI) cascade (10, 43).…”

mentioning

confidence: 99%

“…Several sources and mediators have been identified in Ca 2ϩ signaling in platelets (24,31,43,44). Summarizing the results of multiple studies, the compartmentalized model of [Ca 2ϩ ] i regulation pathways in platelets and MKs consists of a G protein-mediated, protein kinase C (PKC) regulation by phospholipase C␤ (PLC␤) followed by calcium release (stored in the dense tubular system) activating the phosphoinositide (PI) cascade (10,43). The resulting increase in [Ca 2ϩ ] i activates phospholipase A2 (PLA2) and increases thromboxane A 2 (TXA 2 ) production (22).…”

mentioning

confidence: 99%

Acetylsalicylic acid enhances purinergic receptor-mediated outward currents in rat megakaryocytes

Young¹,

Beckerman

Vicini³

et al. 2010

American Journal of Physiology-Cell Physiology

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Young JP, Beckerman J, Vicini S, Myers A. Acetylsalicylic acid enhances purinergic receptor-mediated outward currents in rat megakaryocytes. Am J Physiol Cell Physiol 298: C602-C610, 2010. First published December 30, 2009 doi:10.1152/ajpcell.00422.2009.-Purinergic receptor activation increases cytosolic Ca 2ϩ concentration in a fluctuating fashion, triggering oscillatory outward Ca 2ϩ -activated K ϩ currents in rat megakaryocytes (MKs). Whole cell and nystatinperforated patch-clamp techniques were used to analyze changes in ionic conductance in MK with acetylsalicylic acid (ASA), a cyclooxygenase-1 inhibitor and antithrombotic agent. MKs are a model for platelet reactivity, particularly in ASA treatment failure (ASA resistance). Freshly isolated MKs were incubated 30 min in the absence or presence of 1 mM ASA. Using a K ϩ -rich internal solution, we recorded outward currents in response to 10 M ATP, 10 M ADP, and 5 M 2-methyl-thio-ADP (2MeSADP) in the voltage-clamp mode. Agonist-induced currents decreased in amplitude over time, but this decline was attenuated by ASA in both continuous and repeated agonist challenge, indicating increased MK reactivity with ASA treatment. In separate experiments, heterologous desensitization was observed when MKs were stimulated with ADP after exposure to a thromboxane receptor agonist (U46619), indicating cross talk between thromboxane and purinergic pathways. Different cells, treated with ASA or MRS2179 (P2Y1 receptor antagonist), were stimulated with 2MeSADP. The dose-response curve was shifted to the left in both cases, suggesting increased MK reactivity. ASA also caused an increased interval between currents (delay). ASA attenuated desensitization of purinergic receptors and increased delay, again suggesting cross talk between purinergic and thromboxane pathways. These findings may be relevant to ASA resistance, because individual variations in sensitivity to the multiple effects of ASA on signaling pathways could result in insensitivity to its antiplatelet effects in some patients.platelets; patch clamp; ADP; ATP; thromboxane CARDIOVASCULAR DISEASE IS the leading cause of morbidity and mortality in the United States and developed countries (17, 54). Platelet increased reactivity is a key factor in the development of stroke and ischemic heart disease. Therefore, platelets have become a target for pharmacological treatment of cardiovascular complications after percutaneous coronary intervention (angioplasty and stent implant) (37) as well as in stroke prevention and management. Aspirin has been shown to be effective in the acute phase of recurrent stroke (49), whereas purinergic receptor blockade in the CAPRIE study showed more effectiveness than aspirin with lower side effects such as bleeding (1). The use of drug-eluting stents and dual therapy of cyclooxygenase (COX) inhibitors and purinergic receptor P2Y 12 blockers reduces the incidence of thromboembolism and ischemic episodes but with the adverse outcome of more bleeding occurrence (47, 57). Common platelet evaluation...

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A molecular signaling model of platelet phosphoinositide and calcium regulation during homeostasis and P2Y1 activation

Cited by 75 publications

References 51 publications

Computational Approaches to Studying Thrombus Development

Computational Approaches to Studying Thrombus Development

Modulation and pre-amplification of PAR1 signaling by ADP acting via the P2Y12 receptor during platelet subpopulation formation

Acetylsalicylic acid enhances purinergic receptor-mediated outward currents in rat megakaryocytes

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