Thromboxane synthesis in hypercholesterolemic platelets--on the mechanism of increased thromboxane synthesis.
Thromboxane B2 biosynthesis from arachidonic acid was increased in platelets from hypercholesterolemic rabbits. The enzymic activity of phospholipase A2 which releases arachidonic acid, the precursor for the biosynthesis of thromboxane B2, showed hardly any change in hypercholesterolemic platelets. Phospholipase C and diglyceride lipase activities also were not changed in platelets from hypercholesterolemic rabbits. Furthermore, phospholipid concentration in platelets were not increased in this state. Thus, I conclude that the supply of precursor for thromboxane B2 biosynthesis was not increased in platelets from hypercholesterolemic rabbits as compared to controls. I have clarified this mechanism for the increased thromboxane synthesis. The biosynthesis of prostaglandin H2 and thromboxane B2 were unaffected by superoxide dismutase, xanthine, xanthine oxidase, mannitol, or benzoate in the experiments designed to study the possible involvement of reactive oxygen species. The effect of glutathione, glutathione peroxidase and H2O2 on cyclooxygenase and thromboxane synthetase were studied by using partially purified enzymes and platelet microsomes. Glutathione and glutathione peroxidase inhibited the activity of the cyclooxygenase but did not inhibit that of thromboxane synthetase. H2O2 caused the inactivation of cyclooxygenase, but the addition of H2O2 did not inhibit the formation of thromboxane B2 from prostaglandin H2. An examination of glutathione concentration and glutathione peroxidase activity in platelets from normal and experimentally hypercholesterolemic rabbits demonstrated that both were decreased in platelets from latter group. The observed alterations in glutathione levels and glutathione peroxidase activity are large enough to cause increased thromboxane B2 synthesis in platelets but the possibility that other unidentified factors may also contribute cannot be excluded.
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D005227:Fatty Acids / Q000032:analysis; D005979:Glutathione Peroxidase / Q000032:analysis; D006937:Hypercholesterolemia / Q000378:metabolism*; D008670:Metals / Q000494:pharmacology; D008861:Microsomes / Q000201:enzymology; D010740:Phospholipases / Q000097:blood; D010743:Phospholipids / Q000032:analysis; D011453:Prostaglandins / Q000096:biosynthesis; D011817:Rabbits; D002787:Sterol Esterase / Q000097:blood; D013929:Thromboxane B2 / Q000096:biosynthesis*; D013931:Thromboxanes / Q000096:biosynthesis*
D005227:Fatty Acids; D008670:Metals; D010743:Phospholipids; D011453:Prostaglandins; D013931:Thromboxanes; D013929:Thromboxane B2; D005979:Glutathione Peroxidase; D010740:Phospholipases; D002787:Sterol Esterase