Differential effect of the antidiabetic thiazolidinediones troglitazone and pioglitazone on human platelet aggregation mechanism.
Troglitazone and pioglitazone, antidiabetic thiazolidinediones, are known to improve insulin resistance. However, the effect of these drugs on platelet aggregation remains unclear. The chemical structure of troglitazone contains vitamin E. Accordingly, we studied the effect of troglitazone, pioglitazone, and vitamin E on thrombin-induced platelet aggregation, metabolism of phosphoinositide, protein phosphorylation, protein kinase C (PKC)-alpha and -beta, and phosphatidylinositol (PI) 3-kinase activation in vitro in human platelets. Maximum platelet aggregation by ADP, collagen, and thrombin decreased in the presence of 0.1-1 micromol/l troglitazone and 500 nmol/l vitamin E for 60 min compared with controls. However, pioglitazone did not inhibit ADP-, collagen-, or thrombin-induced platelet aggregation. Pretreatment with troglitazone and vitamin E, but not with pioglitazone, resulted in decreases in thrombin-induced phosphatidic acid production, hydrolysis of phosphatidylinositol 4,5-bisphosphate by phospholipase C, and 47-kDa protein phosphorylation. Thrombin-induced PKC-alpha and -beta activation in membrane fraction was suppressed by pretreatment with troglitazone and vitamin E, but not with pioglitazone. Separately, troglitazone and pioglitazone stimulated PI 3-kinase activity, but thrombin-induced PI 3-kinase activation was suppressed by pretreatment with troglitazone and pioglitazone for 60 min. These results suggest that troglitazone and vitamin E, but not pioglitazone, have a potent inhibitory effect on platelet aggregation via suppression of the thrombin-induced activation of phosphoinositide signaling in human platelets. Finally, the chemical structure of vitamin E may contribute to the inhibitory effect of troglitazone on platelet aggregation in human platelets.
Ishizuka
T
T
Third Department of Internal Medicine, Gifu University School of Medicine, Japan. tishizuk-gif@umin.u-tokyo.ac.jp
Itaya
S
S
Wada
H
H
Ishizawa
M
M
Kimura
M
M
Kajita
K
K
Kanoh
Y
Y
Miura
A
A
Muto
N
N
Yasuda
K
K
D000244:Adenosine Diphosphate / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology*; D003094:Collagen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000097:blood; D007700:Kinetics; D019869:Phosphatidylinositol 3-Kinases / Q000097:blood; D010716:Phosphatidylinositols / Q000097:blood*; D010766:Phosphorylation; D000077205:Pioglitazone; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011493:Protein Kinase C / Q000097:blood; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D013917:Thrombin / Q000494:pharmacology; D000077288:Troglitazone; D014810:Vitamin E / Q000494:pharmacology*
D001798:Blood Proteins; D002839:Chromans; D007004:Hypoglycemic Agents; D007527:Isoenzymes; D010716:Phosphatidylinositols; D010975:Platelet Aggregation Inhibitors; D013844:Thiazoles; D045162:Thiazolidinediones; D014810:Vitamin E; D000244:Adenosine Diphosphate; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; C496628:PRKCA protein, human; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D013917:Thrombin; D000077288:Troglitazone; D000077205:Pioglitazone