Saxatilin, a snake venom disintegrin, regulates platelet activation associated with human vascular endothelial cell migration and invasion.
BACKGROUND
Platelet activation results in platelet aggregation and the secretion of granules, which contain a variety of constituents including nonprotein molecules, adhesive proteins and hydrolases. The platelet-derived supernatant (PDS), which contains these granules, is known to trigger the activation of endothelium and chemotaxis of monocytes.


RESULTS
PDS derived from collagen-activated platelets stimulated human umbilical vein endothelial cell (HUVEC) migration and invasion, as measured through the use of a Boyden chamber. This collagen-induced PDS also triggered integrin alpha(v)beta(3) upregulation in HUVECs. The inclusion of a neutralizing antibody to platelet-derived growth factor (PDGF)-B abolished HUVEC migration/invasion and integrin alpha(v)beta(3) upregulation, showing that PDGF-AB mediates the proangiogenic effects of collagen-activated PDS. Saxatilin, a snake venom disintegrin known to interrupt platelet aggregation by antagonizing integrin alpha(IIb)beta(3), inhibited the collagen-induced platelet activation and abolished the angiogenic properties of PDS. Saxatilin also inhibited the collagen-induced phosphorylation of Syk, a key mediator of inside-out signaling in platelet activation.


CONCLUSIONS
Saxatilin inhibits platelet activation, platelet PDGF-AB release as well as subsequent endothelial cell migration and invasion.
Jang
Yoon-Jung
YJ
Department of Biochemistry, College of Science, Yonsei University, Seoul, Republic of Korea.
Jeon
Ok-Hee
OH
Kim
Doo-Sik
DS
D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology; D019483:Disintegrins / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D000072377:Syk Kinase; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation / Q000187:drug effects
D019483:Disintegrins; D039302:Integrin alphaVbeta3; D047908:Intracellular Signaling Peptides and Proteins; D010975:Platelet Aggregation Inhibitors; D010982:Platelet-Derived Growth Factor; C095477:platelet-derived growth factor AB; C459080:saxatilin; D003094:Collagen; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3