Novel endogenous negative modulators of platelet function as potential anti-thrombotic targets

Y.-J. Li, H.-X. Zhu, D. Zhang, H.-C. Li, P. Ma, L.-Y. Huang

School of Medical Technology, Xuzhou Medical University, Xuzhou, Jiangsu Province, China. huangly1985@163.com

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• Pharmacology

Platelets are megakaryocyte-derived nuclear-free fragments that participate in cardiovascular diseases including acute myocardial infarction, ischemic stroke, hypertension, and atherosclerosis. At the endothelium damage site, platelets interact with sub-endothelial matrix proteins such as glycoprotein VI/Fc receptor γ-chain (GPVI/FcRγ), G protein-coupled receptor/phospholipase Cγ(β) (GPCR/PLCγ(β)), Rho/RhoK and integrin. The activation of these signaling pathways triggers intracellular calcium increase and causes platelet adhesion, aggregation, granule release and finally thrombus formation. Some endogenous platelet modulators reported to negatively regulate this process are: (1) platelet surface inhibitory receptors: carcinoembryonic antigen cell adhesion molecule 1, 2 (CEACAM 1, 2), platelet endothelial cell adhesion molecule-1 (PECAM-1), and G6b-B; (2) nuclear receptors: retinoic X receptor (RXRs), glucocorticoid receptor (GR), peroxisome proliferator-activated receptors (PPARs) and liver X receptors (LXRs); (3) intracellular adaptor proteins: CLP36, paxillin, downstream of tyrosine kinase (Dok), c-Casitas B-lineage lymphoma (c-Cbl), protein kinase Cδ (PKCδ), glycogen synthase kinase(GSK)-3β, phospholipase D2 (PLD2), peroxiredoxin II (PrxII), T-cell ubiquitin ligand-2 (TULA-2); (4) extracellular modulators released from platelet granules: adapter protein disabled-2 (DAB2) and diadenosine 5,5-P1, P2-diphosphate (Ap2A). The discovery of biological or endogenous modulators of platelet activation is regarded as a potential therapeutic target for thrombotic disease. This review highlights the recent findings on the endogenous negative regulatory molecules released from platelets and their impact on platelet thrombus formation.

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