Caspase inhibition of platelet activation.
The role of caspases in platelet function is not well understood. When platelets are activated, they express phosphatidylserine on the outer plasma membrane, form platelet microparticles, and aggregate (Pag). The aims of this study were to determine if caspases play a role in the platelet activation seen in type 2 diabetes. Diabetic rats (Zucker diabetic fatty) were treated with a broad-spectrum caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone, in vivo and platelets were evaluated for phosphatidylserine expression, platelet microparticle formation, and Pag. We found a decreased phosphatidylserine exposure in zVAD-Zucker diabetic fatty rats compared to Zucker diabetic fatty-phosphate-buffered saline when activated with 20 micromol/l ADP. Zucker diabetic fatty rats treated with benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone decreased platelet microparticle numbers compared to phosphate-buffered saline control Zucker diabetic fatty rats. Further, treatment with benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone significantly decreased Pag. These results indicate that caspases play a role in platelet activation, suggesting a unique physiologic role of these proteases and perhaps the underlying mechanisms involved in the chronic platelet activation observed in type 2 diabetes.
Cohen
Zoë
Z
Department of Physiology, University of Arizona, Tucson, Arizona 85721, USA. zcohen@email.arizona.edu
Davis-Gorman
Grace
G
McDonagh
Paul F
PF
Ritter
Leslie
L
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000201:enzymology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000201:enzymology; D015539:Platelet Activation / Q000502:physiology*; D010974:Platelet Aggregation / Q000502:physiology; D051381:Rats; D011924:Rats, Zucker
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; C426824:benzyloxycarbonyl-valyl-alanyl-(methyl)aspartic acid fluoromethyl ketone; D020169:Caspases