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      An Antithrombotic Strategy by Targeting Phospholipase D in Human Platelets

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          Abstract

          Phospholipase D (PLD) is involved in many biological processes. PLD1 plays a crucial role in regulating the platelet activity of mice; however, the role of PLD in the platelet activation of humans remains unclear. Therefore, we investigated whether PLD is involved in the platelet activation of humans. Our data revealed that inhibition of PLD1 or PLD2 using pharmacological inhibitors effectively inhibits platelet aggregation in humans. However, previous studies have showed that PLD1 or PLD2 deletion did not affect mouse platelet aggregation in vitro, whereas only PLD1 deletion inhibited thrombus formation in vivo. Intriguingly, our data also showed that the pharmacological inhibition of PLD1 or PLD2 does not affect mouse platelet aggregation in vitro, whereas the inhibition of only PLD1 delayed thrombus formation in vivo. These findings indicate that PLD may play differential roles in humans and mice. In humans, PLD inhibition attenuates platelet activation, adhesion, spreading, and clot retraction. For the first time, we demonstrated that PLD1 and PLD2 are essential for platelet activation in humans, and PLD plays different roles in platelet function in humans and mice. Our findings also indicate that targeting PLD may provide a safe and alternative therapeutic approach for preventing thromboembolic disorders.

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          Most cited references25

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          The phospholipase D superfamily as therapeutic targets.

          The phospholipase D (PLD) lipid-signaling enzyme superfamily has long been studied for its roles in cell communication and a wide range of cell biological processes. With the advent of loss-of-function genetic mouse models that have revealed that PLD1 and PLD2 ablation is overtly tolerable, small-molecule PLD1/2 inhibitors that do not cause unacceptable clinical toxicity, a PLD2 polymorphism that has been linked to altered physiology, and growing delineation of processes that are subtly altered in mice lacking PLD1/2 activity, the stage is being set for assessment of PLD1/2 inhibition for therapeutic purposes. Based on findings to date, PLD1/2 inhibition may be of more utility in acute rather than chronic settings, although this generalization will depend on the specific risks and benefits in each disease setting.
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            Two distinct roles of mitogen-activated protein kinases in platelets and a novel Rac1-MAPK-dependent integrin outside-in retractile signaling pathway.

            Mitogen-activated protein kinases (MAPK), p38, and extracellular stimuli-responsive kinase (ERK), are acutely but transiently activated in platelets by platelet agonists, and the agonist-induced platelet MAPK activation is inhibited by ligand binding to the integrin alpha(IIb)beta(3). Here we show that, although the activation of MAPK, as indicated by MAPK phosphorylation, is initially inhibited after ligand binding to integrin alpha(IIb)beta(3), integrin outside-insignaling results in a late but sustained activation of MAPKs in platelets. Furthermore, we show that the early agonist-induced MAPK activation and the late integrin-mediated MAPK activation play distinct roles in different stages of platelet activation. Agonist-induced MAPK activation primarily plays an important role in stimulating secretion of platelet granules, while integrin-mediated MAPK activation is important in facilitating clot retraction. The stimulatory role of MAPK in clot retraction is mediated by stimulating myosin light chain (MLC) phosphorylation. Importantly, integrin-dependent MAPK activation, MAPK-dependent MLC phosphorylation, and clot retraction are inhibited by a Rac1 inhibitor and in Rac1 knockout platelets, indicating that integrin-induced activation of MAPK and MLC and subsequent clot retraction is Rac1-dependent. Thus, our results reveal 2 different activation mechanisms of MAPKs that are involved in distinct aspects of platelet function and a novel Rac1-MAPK-dependent cell retractile signaling pathway.
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              A molecular switch that controls cell spreading and retraction

              Integrin-dependent cell spreading and retraction are required for cell adhesion, migration, and proliferation, and thus are important in thrombosis, wound repair, immunity, and cancer development. It remains unknown how integrin outside-in signaling induces and controls these two opposite processes. This study reveals that calpain cleavage of integrin β3 at Tyr759 switches the functional outcome of integrin signaling from cell spreading to retraction. Expression of a calpain cleavage–resistant β3 mutant in Chinese hamster ovary cells causes defective clot retraction and RhoA-mediated retraction signaling but enhances cell spreading. Conversely, a calpain-cleaved form of β3 fails to mediate cell spreading, but inhibition of the RhoA signaling pathway corrects this defect. Importantly, the calpain-cleaved β3 fails to bind c-Src, which is required for integrin-induced cell spreading, and this requirement of β3-associated c-Src results from its inhibition of RhoA-dependent contractile signals. Thus, calpain cleavage of β3 at Tyr759 relieves c-Src–mediated RhoA inhibition, activating the RhoA pathway that confines cell spreading and causes cell retraction.
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                Author and article information

                Journal
                J Clin Med
                J Clin Med
                jcm
                Journal of Clinical Medicine
                MDPI
                2077-0383
                14 November 2018
                November 2018
                : 7
                : 11
                : 440
                Affiliations
                [1 ]Department of Medical Research, Taipei Medical University Hospital, Taipei 110, Taiwan; luwj@ 123456tmu.edu.tw
                [2 ]Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; tiffany4441@ 123456gmail.com (L.T.H.); change@ 123456seed.net.tw (C.C.C.)
                [3 ]Graduate Institute of Metabolism and Obesity Sciences, College of Public Health and Nutrition, Taipei Medical University, Taipei 110, Taiwan
                [4 ]Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 110, Taiwan; clchung@ 123456tmu.edu.tw
                [5 ]School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
                [6 ]Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei 110, Taiwan; rayjchen@ 123456tmu.edu.tw
                [7 ]School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; m002177@ 123456ms.skh.org.tw
                [8 ]Department of Neurology, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan
                [9 ]Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan
                [10 ]Institute of Biomedical Sciences, Mackay Medical College, New Taipei City 252, Taiwan
                [11 ]Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
                Author notes
                [* ]Correspondence: linkh@ 123456mmc.edu.tw (K.H.L.); sheujr@ 123456tmu.edu.tw (J.R.S.); Tel.: +886-2-26360303 (ext. 1726) (K.H.L.); +886-2-27361661 (ext. 3199) (J.R.S.)
                Author information
                https://orcid.org/0000-0003-0656-976X
                https://orcid.org/0000-0003-1519-1797
                Article
                jcm-07-00440
                10.3390/jcm7110440
                6262437
                30441821
                822bd314-1022-4233-b342-5f53e34904fa
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 12 October 2018
                : 13 November 2018
                Categories
                Article

                phospholipase d,platelet activation,clot retraction,thrombus formation

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