Mechanism of platelet functional changes and effects of anti-platelet agents on in vivo hemostasis under different gravity conditions.
Serious thrombotic and hemorrhagic problems or even fatalities evoked by either microgravity or hypergravity occur commonly in the world. We recently reported that platelet functions are inhibited in microgravity environments and activated under high-G conditions, which reveals the pathogenesis for gravity change-related hemorrhagic and thrombotic diseases. However, the mechanisms of platelet functional variations under different gravity conditions remain unclear. In this study we show that the amount of filamin A coimmunoprecipitated with GPIbalpha was enhanced in platelets exposed to modeled microgravity and, in contrast, was reduced in 8 G-exposed platelets. Hypergravity induced actin filament formation and redistribution, whereas actin filaments were reduced in platelets treated with modeled microgravity. Furthermore, intracellular Ca2+ levels were elevated by hypergravity. Pretreatment of platelets with the cell-permeable Ca2+ chelator BAPTA-AM had no effect on cytoskeleton reorganization induced by hypergravity but significantly reduced platelet aggregation induced by ristocetin/hypergravity. Two anti-platelet agents, aspirin and tirofiban, effectively reversed the shortened tail bleeding time and reduced the death rate of mice exposed to hypergravity. Furthermore, the increased P-selectin surface expression was obviously reduced in platelets from mice treated with aspirin/hypergravity compared with those from mice treated with hypergravity alone. These data suggest that the actin cytoskeleton reorganization and intracellular Ca2+ level play key roles in the regulation of platelet functions in different gravitational environments. The results with anti-platelet agents not only further confirm the activation of platelets in vivo but also suggest a therapeutic potential for hypergravity-induced thrombotic diseases.
Li
Suping
S
School of Biological Science and Medical Engineering, Beihang University, 37 Xueyuan Road, Haidian district, Beijing 100083, China.
Shi
Quanwei
Q
Liu
Guanglei
G
Zhang
Weilin
W
Wang
Zhicheng
Z
Wang
Yuedan
Y
Dai
Kesheng
K
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000244:Adenosine Diphosphate; D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000097:blood; D002614:Chelating Agents / Q000494:pharmacology; D003285:Contractile Proteins / Q000097:blood; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D064448:Filamins; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D018471:Hypergravity; D008562:Membrane Glycoproteins / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000097:blood; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019038:Platelet Glycoprotein GPIb-IX Complex; D011485:Protein Binding; D012310:Ristocetin; D013927:Thrombosis / Q000097:blood / Q000517:prevention & control*; D013997:Time Factors; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018474:Weightlessness Simulation
D002614:Chelating Agents; D003285:Contractile Proteins; D064448:Filamins; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D010975:Platelet Aggregation Inhibitors; D019038:Platelet Glycoprotein GPIb-IX Complex; C094990:adhesion receptor; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D012310:Ristocetin; D014443:Tyrosine; D004533:Egtazic Acid; D000244:Adenosine Diphosphate; D000077466:Tirofiban; D001241:Aspirin; D002118:Calcium