Glutathione regulates integrin alpha(IIb)beta(3)-mediated cell adhesion under flow conditions.
The platelet integrin alpha(IIb)beta(3) mediates the final step of platelet aggregation that requires pre-activation through an inside-out signal initiated by agonists. Experiments conducted under static conditions using platelet-rich plasma show that platelet activation and adhesion activity of alpha(IIb)beta(3) are regulated by glutathione (GSH-GSSG) redox potential. However, it remains unclear as to whether GSH-GSSG exerts its regulatory role in platelets by direct targeting of alpha(IIb)beta(3) or intracellular signals that activate the integrin. A role of fluid shear stress is also not known. We examined the effects of GSH-GSSG on the adhesion of CHO cells expressing two HPA variants of human alpha(IIb)beta(3) to the immobilized fibrinogen and von Willebrand factor (VWF) under flow conditions. GSH-GSSG dose-dependently reduced the number of adherent cells to fibrinogen and VWF under 2.5 dyn/cm(2) of shear stress, a physical force calculated to be 110 dyne on platelets. GSH treatment also abolished the hyper-adhesion activity of cells expressing the Pro33 variant of alpha(IIb)beta(3). The inhibition was also observed with washed platelets. The data differ from the early observation that GSH enhanced platelet aggregation induced by sub-threshold concentrations of platelet agonists. The results suggest that GSH may have distinct effects on agonist-induced alpha(IIb)beta(3) activation and on the alpha(IIb)beta(3)-fibrinogen or alpha(IIb)beta(3)-VWF bonds when exposed to fluid shear stress. They further suggest that the HPA phenotype may be redox-regulated.
Ball
Chalmette
C
Thrombosis Research Section, Department of Medicine, Medicine Baylor College of Medicine, BCM286, N1319 One Baylor Plaza, Houston, Texas 77030, USA.
Vijayan
K Vinod
KV
Nguyen
Trung
T
Anthony
Kim
K
Bray
Paul F
PF
Essex
David W
DW
Dong
Jing-Fei
JF
D000818:Animals; D016824:Antigens, Human Platelet / Q000378:metabolism; D016466:CHO Cells; D002448:Cell Adhesion; D006224:Cricetinae; D003412:Cricetulus; D005340:Fibrinogen / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism; D018056:Hemorheology; D006801:Humans; D039661:Integrin beta3; D010084:Oxidation-Reduction; D010973:Platelet Adhesiveness; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms; D011673:Pulsatile Flow; D013314:Stress, Mechanical; D014162:Transfection; D014841:von Willebrand Factor / Q000378:metabolism
D016824:Antigens, Human Platelet; C061248:ITGB3 protein, human; D039661:Integrin beta3; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D020033:Protein Isoforms; C083451:human platelet antigen 1b; D014841:von Willebrand Factor; D005340:Fibrinogen; D005978:Glutathione; D019803:Glutathione Disulfide