Platelet hypersensitivity in cholesterol-fed rabbits: enhancement of thromboxane A2-dependent and thrombin-induced, thromboxane A2-independent platelet responses.
Hypercholesterolemia (mean plasma cholesterol: 15 mM) was induced in rabbits by the feeding of a chow diet enriched with a low amount (0.25%, w/w) of cholesterol only. Platelet size and protein content decreased significantly, but the whole blood platelet count did not change. The platelets became enriched in cholesterol, as indicated by a significant increase in the cholesterol:phospholipid molar (C/P) ratio. Specific responses of washed platelets stimulated with various agonists were studied to determine the effects of hypercholesterolemia on the various pathways of platelet aggregation in the absence of plasma components. In platelets from hypercholesterolemic rabbits compared with controls: aggregation induced by ADP was not altered; collagen-induced responses (aggregation, secretion of [14C]serotonin from prelabelled platelets, thromboxane A2 (TXA2) formation, mobilization of [3H]arachidonate from prelabelled platelets) were enhanced; with aspirin-treated platelets, aggregation induced by the TXA2 mimetic U46619 was enhanced: and thrombin-induced responses of both untreated platelets (aggregation, secretion of granule contents, TXA2 formation) and aspirin-treated platelets (aggregation) were enhanced. Thus, platelets from cholesterol-fed rabbits not only form more TXA2, but they aggregate more extensively when stimulated by its mimetic. In addition, it has not been previously recognized that these platelets are also hypersensitive to thrombin-induced aggregation that is independent of TXA2.
Gross
P L
PL
Department of Biochemistry, University of Toronto, Ontario, Canada.
Rand
M L
ML
Barrow
D V
DV
Packham
M A
MA
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D002784:Cholesterol / Q000097:blood; D003094:Collagen / Q000494:pharmacology; D006937:Hypercholesterolemia / Q000097:blood*; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010976:Platelet Count; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011817:Rabbits; D012701:Serotonin / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000096:biosynthesis
D011450:Prostaglandin Endoperoxides, Synthetic; D012701:Serotonin; D013929:Thromboxane B2; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D003094:Collagen; D002784:Cholesterol; D013917:Thrombin; D001241:Aspirin