摘要
血栓的形成严重影响了人类的健康,迄今为止尚未明确其形成机制。研究发现,血小板上的一种受体GPIbα,在血栓的形成中发挥重要作用。GPIbα通过与凝血酶和VWF的结合而激活血小板,是促成血栓的形成的主要途径;结合位点位于GPIbα的265-288残基区域,并受到其他区域的调节。其他途径,如GPIbα的膜外功能区脱落形成s GPIb,同样也会对血栓的形成造成影响。体内多种因素的影响,如PARs、ADAM-17和14-3-3ζ等,会对GPIbα的生理功能造成影响,并最终影响了血栓的形成。本文主要对目前基于GPIbα受体的血栓形成研究成果,对GPIbα的结构、功能和介导血栓形成的机制作一综述,期望对血栓形成和治疗的进一步研究起到一定的帮助。
The thrombosis disease is a serious hazard to human health, but the mechanism of it was not clear. It has been reported that GPIbα, one of the receptors on platelet, is crucial in thrombosis disease. Platelet activation is of critical importance for the mechanism of thrombosis disease, mediated by the binding of thrombin and VWF to GPIbα. The binding sites locate on the 265-288 residues of GPIbα and the binding is regulated by other regions of GPIbα. In addition, other approaches, such as s GPIb caused by ectodomain shedding of GPIbα, also lead to thrombosis disease. The function of GPIbα is affected by some factors like PARs,ADAM-17, 14-3-3ζ and so on. Recent researches of the construction, function and mechanism of GPIb α were reviewed in this article.The purpose of this review is to provide new ways to explore the mechanism and treatment of thrombosis disease.
引文
[1]Mavrakanas T,Bounameaux H.The potential role of new oral anticoagulants in the prevention and treatment of thromboembolism[J].Pharmacol Ther,2011,130(1):46-58
[2]Clemetson KJ.Platelets and primary haemostasis[J].Thromb Res,2012,129(3):220-224
[3]Andrews RK,Berndt MC.Bernard-Soulier syndrome:an update[J].Semin Thromb Hemost,2013,39(6):656-662
[4]Du X.Signaling and regulation of the platelet glycoprotein Ib-IX-V complex[J].Curr Opin Hematol,2007,14(3):262-269
[5]Zarpellon A,Celikel R,Roberts JR,et al.Binding of alpha-thrombin to surface-anchored platelet glycoprotein Ib(alpha)sulfotyrosines through a two-site mechanism involving exosite I[J].Proc Natl Acad Sci U S A,2011,108(21):8628-8633
[6]Li R,Emsley J.The organizing principle of the platelet glycoprotein Ib-IX-V complex[J].J Thromb Haemost,2013,11(4):605-614
[7]Miszta A,Pelkmans L,Lindhout T,et al.Thrombin-dependent Incorporation of von Willebrand Factor into a Fibrin Network[J].J Biol Chem,2014,289(52):35979-35986
[8]Lechtenberg BC,Freund SM,Huntington JA.Gp Ibαinteracts exclusively with exosite II of thrombin[J].J Mol Bio,2014,426(4):881-893
[9]Mehta AY,Thakkar JN,Mohammed BM,et al.Targeting the GPIbαbinding site of thrombin to simultaneously induce dual anticoagulant and antiplatelet effects[J].J Med Chem,2014,57(7):3030-3039
[10]Asokananthan N,Lan RS,Graham PT.Activation of proteaseactivated receptors(PARs)-1 and-2 promotes alpha-smooth muscle actin expression and release of cytokines from human lung fibroblasts[J].Physiol Rep,2015,3(2):pii:e12295
[11]De Candia E,Hall SW,Rutella S,et al.Binding of thrombin to glycoprotein Ib accelerates the hydrolysis of Par-1 on intact platelets[J].J Biol Chem,2001,276(7):4692-4698
[12]Malovichko MV,Sabo TM,Maurer MC.Ligand binding to anionbinding exosites regulates conformational properties of thrombin[J].J Biol Chem,2013,288(12):8667-8678
[13]Schinco P,Cultrera D,Valeri F,et al.Cost-consequence analysis of long-term prophylaxis in the treatment of von Willebrand disease in the Italian context[J].Clinicoecon Outcomes Res,2014,7:17-25
[14]Bryckaert M,Rosa JP,Denis CV,et al.Of von Willebrand factor and platelets[J].Cell Mol Life Sci,2015,72(2):307-326
[15]Tait AS,Dong JF,López JA,et al.Site-directed mutagenesis of platelet glycoprotein Ib alpha demonstrating residues involved in the sulfation of tyrosines 276,278,and 279[J].Blood,2002,99(12):4422-4427
[16]Peng Y,Berndt MC,Cruz MA,et al.The alpha1 helix-beta13 strand spanning Leu214 to Val229 of platelet glycoprotein Ibalpha facilitates the interaction with von Willebrand factor:evidence from characterization of the epitope of monoclonal antibody AP1[J].Blood,2004,104(13):3971-3978
[17]Clemetson KJ.Platelets and primary haemostasis[J].Thromb Res,2012,129(3):220-224
[18]Navdaev A,Subramanian H,Petunin A,et al.Echicetin coated polystyrene beads:a novel tool to investigate GPIb-specific platelet activation and aggregation[J].PLo S One,2014,9(4):e93569
[19]Dai K,Bodnar R,Berndt MC,et al.A critical role for 14-3-3zeta protein in regulating the VWF binding function of platelet glycoprotein Ib-IX and its therapeutic implications[J].Blood,2005,106(6):1975-1981
[20]Cranmer SL,Ashworth KJ,Yao Y,et al.High shear-dependent loss of membrane integrity and defective platelet adhesion following disruption of the GPIbalpha-filamin interaction[J].Blood,2011,117(9):2718-2727
[21]Berrou E,Adam F,Lebret M,et al.Heterogeneity of platelet functional alterations in patients with filamin A mutations[J].Arterioscler Thromb Vasc Biol,2013,33(1):e11-18
[22]Montoro-García S,Shantsila E,Orenes-Pi觡ero E,et al.An innovative flow cytometric approach for small-size platelet microparticles:influence of calcium[J].Thromb Haemost,2012,108(2):373-383
[23]Bergmeier W,Piffath CL,Cheng G,Dole VS,et al.Tumor necrosis factor-alpha-converting enzyme(ADAM17)mediates GPIbalpha shedding from platelets in vitro and in vivo[J].Circ Res,2004,95(7):677-683
[24]Gardiner EE,Karunakaran D,Shen Y,et al.Controlled shedding of platelet glycoprotein(GP)VI and GPIb-IX-V by ADAM family metalloproteinases[J].J Thromb Haemost,2007,5(7):1530-1537
[25]Zhang P,Du J,Zhao L,et al.The role of intraplatelet reactive oxygen species in the regulation of platelet glycoprotein Ibαectodomain shedding[J].Thromb Res,2013,132(6):696-701
[26]Berndt MC,Metharom P,Andrews RK.Primary haemostasis newer insights[J].Haemophilia,2014,20 Suppl 4:15-21
[27]Brill A,Chauhan AK,Canault M,et al.Oxidative stress activates ADAM17/TACE and induces its target receptor shedding in platelets in a p38-dependent fashion[J].Cardiovasc Res,2009,84(1):137-144
[28]Liu X,Yan Y,Bao L,et al.Ginkgolide B inhibits platelet release by blocking Syk and p38 MAPK phosphorylation in thrombin-stimulated platelets[J].Thromb Res,2014,134(5):1066-1073
[29]Liang Y,Li X,Zhang X,et al.Elevated levels of plasma TNF-αare associated with microvascular endothelial dysfunction in patients with sepsis through activating the NF-κB and p38 mitogen-activated protein kinase in endothelial cells[J].Shock,2014,41(4):275-281
[30]Mo X,Nguyen NX,Mu FT,et al.Transmembrane and trans-subunit regulation of ectodomain shedding of platelet glycoprotein Ibalpha[J].J Biol Chem,2010,285(42):32096-32104
