Computational biology analysis of platelet signaling reveals roles of feedbacks through phospholipase C and inositol 1,4,5-trisphosphate 3-kinase in controlling amplitude and duration of calcium oscillations

Balabin, F. A.; Sveshnikova, Anastasia N.

doi:10.1016/j.mbs.2016.03.006

Cited by 18 publications

(8 citation statements)

References 51 publications

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“…Platelets play a critical role in hemostasis and their major purpose is to plug the injuries in the vessel walls. They are also an important contributor in the development of abnormal thrombosis that is related to the cardiovascular diseases [ 15 ]. Despite the existence of a well know antithrombotic remedies with a proven efficacy, the research of novel bioactive natural products interfering with platelets and/or plasmatic coagulation is increasingly intense.…”

Section: Discussionmentioning

confidence: 99%

Effects of Juglans regia Root Bark Extract on Platelet Aggregation, Bleeding Time, and Plasmatic Coagulation: In Vitro and Ex Vivo Experiments

Amirou

Bnouham

Legssyer

et al. 2018

Evidence-Based Complementary and Alternative Medicine

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Platelets have an important role in thrombosis and haemostasis. Hyperactivity of the platelets has been associated with thromboembolic diseases and represents the main cause of complications of cardiovascular diseases. Crude aqueous extract (CAE) of Juglans regia root bark was evaluated for bleeding time, antiaggregant activity by using agonists, thrombin, ADP, collagen, or arachidonic acid (in vitro and ex vivo), and anticoagulant activity by measuring the clotting parameters: activated partial thromboplastin time, prothrombin time, thrombin time, and fibrinogen dosage (in vitro and ex vivo). The result of this study reported that the strongest antiaggregant effect of CAE in vitro was observed on the ADP-induced aggregation with inhibitions up to 90 %, while, in ex vivo experiments, the inhibition (more than 80 %) was observed with all agonists. Anticoagulant effect of CAE significantly prolonged the TT and decreased the fibrinogen level in vitro and ex vivo without interfering with APTT and PT. The bleeding time in mice and rats was significantly increased by CAE. The antiplatelet and anticoagulant effect observed in this study suggest that Juglans regia could have antithrombotic and/or thrombolytic activities and provide an alternative therapy against thrombotic complications related to cardiovascular diseases.

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Section: Discussionmentioning

confidence: 99%

Effects of Juglans regia Root Bark Extract on Platelet Aggregation, Bleeding Time, and Plasmatic Coagulation: In Vitro and Ex Vivo Experiments

Amirou

Bnouham

Legssyer

et al. 2018

Evidence-Based Complementary and Alternative Medicine

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“…This step has several layers of complexity. The effects of various agonists (beginning with collagen itself) and antagonists are integrated by tens of platelet receptors initiating several intracellular signalling cascades in a decision-making task of immense complexity [14,15,23]. As a result of this huge reaction network action, platelets undergo transition to various activation states, associated with a hierarchy of responses.…”

Section: Hemostasis and Arterial Thrombosis: From Physics To Physiologymentioning

confidence: 99%

Modeling thrombosis in silico: Frontiers, challenges, unresolved problems and milestones

Belyaev

Dunster

Gibbins

et al. 2018

Physics of Life Reviews

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Hemostasis is a complex physiological mechanism that functions to maintain vascular integrity under any conditions. Its primary components are blood platelets and a coagulation network that interact to form the hemostatic plug, a combination of cell aggregate and gelatinous fibrin clot that stops bleeding upon vascular injury. Disorders of hemostasis result in bleeding or thrombosis, and are the major immediate cause of mortality and morbidity in the world. Regulation of hemostasis and thrombosis is immensely complex, as it depends on blood cell adhesion and mechanics, hydrodynamics and mass transport of various species, huge signal transduction networks in platelets, as well as spatiotemporal regulation of the blood coagulation network. Mathematical and computational modeling has been increasingly used to gain insight into this complexity over the last 30 years, but the limitations of the existing models remain profound. Here we review state-of-the-art-methods for computational modeling of thrombosis with the specific focus on the analysis of unresolved challenges. They include: a) fundamental issues related to physics of platelet aggregates and fibrin gels; b) computational challenges and limitations for solution of the models that combine cell adhesion, hydrodynamics and chemistry; c) biological mysteries and unknown parameters of processes; d) biophysical complexities of the spatiotemporal networks' regulation. Both relatively classical approaches and innovative computational techniques for their solution are considered; the subjects discussed with relation to thrombosis modeling include coarse-graining, continuum versus particle-based modeling, multiscale models, hybrid models, parameter estimation and others. Fundamental understanding gained from theoretical models are highlighted and a description of future prospects in the field and the nearest possible aims are given.

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“…We recently used a computational systems biology approach to propose a comprehensive picture of platelet subpopulation development; the model of calcium platelet signaling predicted that platelet stimulation via PAR1 produced cytosolic calcium spikes to become taken up by mitochondria, leading to their overload and mPTP opening in some platelets ; however, this still remains to be tested. The relationship between calcium dynamics, mitochondrial collapse and PS exposure in single platelets of different subpopulations has not been carefully elucidated experimentally, and this was the purpose of the present study.…”

Section: Introductionmentioning

confidence: 99%

Dynamics of calcium spiking, mitochondrial collapse and phosphatidylserine exposure in platelet subpopulations during activation

Obydennyy

Sveshnikova

Ataullakhanov

et al. 2016

Journal of Thrombosis and Haemostasis

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To cite this article: Obydennyy SI, Sveshnikova AN, Ataullakhanov FI, Panteleev MA. Dynamics of calcium spiking, mitochondrial collapse and phosphatidylserine exposure in platelet subpopulations during activation. J Thromb Haemost 2016; 14: 1867-81. Essentials• The sequence and logic of events leading to platelet procoagulant activity are poorly understood.• Confocal time-lapse microscopy was used to investigate activation of single adherent platelets.• Platelet transition to the procoagulant state followed cytosolic calcium oscillations.• Mitochondria did not collapse simultaneously and membrane potential loss could be reversible.Summary. Background: Activated platelets form two subpopulations, one of which is able to efficiently aggregate, and another that externalizes phosphatidylserine (PS) and thus accelerates membrane-dependent reactions of blood coagulation. The latter, procoagulant subpopulation is characterized by a high cytosolic calcium level and the loss of inner mitochondrial membrane potential, and there are conflicting opinions on their roles in its formation. Methods: We used confocal microscopy to investigate the dynamics of subpopulation formation by imaging single, fibrinogen-bound platelets with individual mitochondria in them upon loading with calcium-sensitive and mitochondrial potential-sensitive dyes. Stimulation was performed with thrombin or the proteaseactivated receptor (PAR) 1 agonist SFLLRN. Stochastic simulations with a computational systems biology model of PAR1 calcium signaling were employed for analysis. Results: Platelet activation resulted in a series of cytosolic calcium spikes and mitochondrial calcium uptake in all platelets. The frequency of spikes decreased with time for SFLLRN stimulation, but remained high for a long period of time for thrombin. In some platelets, uptake of calcium by mitochondria led to the mitochondrial permeability transition pore opening and inner mitochondrial membrane potential loss, which could be either reversible or irreversible. The latter resulted in an increase in the cytosolic calcium level and PS exposure. These platelets had higher cytosolic calcium levels before activation, and their mitochondria collapsed not simultaneously but one after another. Conclusions: These results support a model of procoagulant subpopulation development following a series of stochastic cytosolic calcium spikes that are accumulated by mitochondria, leading to a collapse, and suggest important roles of individual platelet reactivity and signal exchange between different mitochondria of a platelet.

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Computational biology analysis of platelet signaling reveals roles of feedbacks through phospholipase C and inositol 1,4,5-trisphosphate 3-kinase in controlling amplitude and duration of calcium oscillations

Cited by 18 publications

References 51 publications

Effects of Juglans regia Root Bark Extract on Platelet Aggregation, Bleeding Time, and Plasmatic Coagulation: In Vitro and Ex Vivo Experiments

Effects of Juglans regia Root Bark Extract on Platelet Aggregation, Bleeding Time, and Plasmatic Coagulation: In Vitro and Ex Vivo Experiments

Modeling thrombosis in silico: Frontiers, challenges, unresolved problems and milestones

Dynamics of calcium spiking, mitochondrial collapse and phosphatidylserine exposure in platelet subpopulations during activation

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