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      Platelet Shape Changes and Cytoskeleton Dynamics as Novel Therapeutic Targets for Anti-Thrombotic Drugs

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          Abstract

          Platelets play an essential role in hemostasis through aggregation and adhesion to vascular injury sites but their unnecessary activation can often lead to thrombotic diseases. Upon exposure to physical or biochemical stimuli, remarkable platelet shape changes precede aggregation or adhesion. Platelets shape changes facilitate the formation and adhesion of platelet aggregates, but are readily reversible in contrast to the irrevocable characteristics of aggregation and adhesion. In this dynamic phenomenon, complex molecular signaling pathways and a host of diverse cytoskeleton proteins are involved. Platelet shape change is easily primed by diverse pro-thrombotic xenobiotics and stimuli, and its inhibition can modulate thrombosis, which can ultimately contribute to the development or prevention of thrombotic diseases. In this review, we discussed the current knowledge on the mechanisms of platelet shape change and also pathological implications and therapeutic opportunities for regulating the related cytoskeleton dynamics.

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          The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly.

          Rajat Rohatgi, Le Ma, Hiroaki Miki … (1999)
          Although small GTP-binding proteins of the Rho family have been implicated in signaling to the actin cytoskeleton, the exact nature of the linkage has remained obscure. We describe a novel mechanism that links one Rho family member, Cdc42, to actin polymerization. N-WASP, a ubiquitously expressed Cdc42-interacting protein, is required for Cdc42-stimulated actin polymerization in Xenopus egg extracts. The C terminus of N-WASP binds to the Arp2/3 complex and dramatically stimulates its ability to nucleate actin polymerization. Although full-length N-WASP is less effective, its activity can be greatly enhanced by Cdc42 and phosphatidylinositol (4,5) bisphosphate. Therefore, N-WASP and the Arp2/3 complex comprise a core mechanism that directly connects signal transduction pathways to the stimulation of actin polymerization.
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            Nanoparticle-induced platelet aggregation and vascular thrombosis.

            Anna Radomski, Paul Jurasz, David Alonso-Escolano … (2005)
            Ever increasing use of engineered carbon nanoparticles in nanopharmacology for selective imaging, sensor or drug delivery systems has increased the potential for blood platelet-nanoparticle interactions. We studied the effects of engineered and combustion-derived carbon nanoparticles on human platelet aggregation in vitro and rat vascular thrombosis in vivo. Multiplewall (MWNT), singlewall (SWNT) nanotubes, C60 fullerenes (C60CS) and mixed carbon nanoparticles (MCN) (0.2-300 microg ml(-1)) were investigated. Nanoparticles were compared with standard urban particulate matter (SRM1648, average size 1.4 microm). Platelet function was studied using lumi aggregometry, phase-contrast, immunofluorescence and transmission electron microscopy, flow cytometry, zymography and pharmacological inhibitors of platelet aggregation. Vascular thrombosis was induced by ferric chloride and the rate of thrombosis was measured, in the presence of carbon particles, with an ultrasonic flow probe. Carbon particles, except C60CS, stimulated platelet aggregation (MCN>or=SWNT>MWNT>SRM1648) and accelerated the rate of vascular thrombosis in rat carotid arteries with a similar rank order of efficacy. All particles resulted in upregulation of GPIIb/IIIa in platelets. In contrast, particles differentially affected the release of platelet granules, as well as the activity of thromboxane-, ADP, matrix metalloproteinase- and protein kinase C-dependent pathways of aggregation. Furthermore, particle-induced aggregation was inhibited by prostacyclin and S-nitroso-glutathione, but not by aspirin. Thus, some carbon nanoparticles and microparticles have the ability to activate platelets and enhance vascular thrombosis. These observations are of importance for the pharmacological use of carbon nanoparticles and pathology of urban particulate matter.
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              WAVE, a novel WASP-family protein involved in actin reorganization induced by Rac.

              S Suetsugu, H Miki, T Takenawa (1998)
              Rac is a Rho-family small GTPase that induces the formation of membrane ruffles. However, it is poorly understood how Rac-induced reorganization of the actin cytoskeleton, which is essential for ruffle formation, is regulated. Here we identify a novel Wiskott-Aldrich syndrome protein (WASP)-family protein, WASP family Verprolin-homologous protein (WAVE), as a regulator of actin reorganization downstream of Rac. Ectopically expressed WAVE induces the formation of actin filament clusters that overlap with the expressed WAVE itself. In this actin clustering, profilin, a monomeric actin-binding protein that has been suggested to be involved in actin polymerization, was shown to be essential. The expression of a dominant-active Rac mutant induces the translocation of endogenous WAVE from the cytosol to membrane ruffling areas. Furthermore, the co-expression of a deltaVPH WAVE mutant that cannot induce actin reorganization specifically suppresses the ruffle formation induced by Rac, but has no effect on Cdc42-induced actin-microspike formation, a phenomenon that is also known to be dependent on rapid actin reorganization. The deltaVPH WAVE also suppresses membrane-ruffling formation induced by platelet-derived growth factor in Swiss 3T3 cells. Taken together, we conclude that WAVE plays a critical role downstream of Rac in regulating the actin cytoskeleton required for membrane ruffling.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Biomol Ther (Seoul)
                Journal ID (iso-abbrev): Biomol Ther (Seoul)
                Journal ID (publisher-id): Biomol Ther (Seoul)
                Journal ID (publisher-id): ksp
                Title: Biomolecules & Therapeutics
                Publisher: The Korean Society of Applied Pharmacology
                ISSN (Print): 1976-9148
                ISSN (Electronic): 2005-4483
                Publication date (Print): May 2017
                Publication date (Electronic): 25 November 2016
                Volume: 25
                Issue: 3
                Pages: 223-230
                Affiliations
                [1 ]College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
                [2 ]College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
                [3 ]Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
                Author notes
                [* ]Corresponding Authors: E-mail: kmlim@ 123456ewha.ac.kr (Lim KM), nohj16@ 123456kribb.re.kr (Noh JY), Tel: +82-2-3277-3055 (Lim KM), +82-42-860-4655(Noh JY), Fax: +82-2-3277-3760 (Lim KM), +82-42-879-8239 (Noh JY)
                Article
                Publisher ID: bt-25-223
                DOI: 10.4062/biomolther.2016.138
                PMC ID: 5424631
                PubMed ID: 27871158
                SO-VID: f2a88a7f-a74f-48fe-b73b-59f424e05739
                Copyright © Copyright ©2017, The Korean Society of Applied Pharmacology
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 27 June 2016
                Date revision received : 27 August 2016
                Date accepted : 01 September 2016
                Categories
                Subject: Review

                Keywords: platelet shape changes,cytoskeleton dynamics,thrombosis,aggregation,adhesion
                Data availability:
                Keywords: platelet shape changes, cytoskeleton dynamics, thrombosis, aggregation, adhesion

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