title: AMP-Activated Protein Kinase Mediates the Antiplatelet Effects of the Thiazolidinediones Rosiglitazone and Pioglitazone.
abstract: The thiazolidinedione antidiabetic drugs rosiglitazone and pioglitazone exert antiplatelet effects. Such effects are known to be mediated by the peroxisome proliferator-activated receptor γ (PPARγ), an acknowledged target of the thiazolidinediones, although the molecular mechanism is elusive. Recently, AMP-activated protein kinase (AMPK) signaling was reported to inhibit platelet aggregation. Because AMPK is another target of the thiazolidinediones, the impact of rosiglitazone and pioglitazone on platelet AMPK and its involvement in aggregation were investigated to assess the contribution of AMPK to the antiplatelet activity of these agents. Treatment with rosiglitazone stimulated both AMPK and PPARγ in isolated rat platelets. However, the concentration and the treatment time required for activation were distinct from each other. Indeed, stimulation of AMPK and PPARγ were discrete events without any cross-activation in platelets. Activation of AMPK or PPARγ by rosiglitazone rendered platelets less responsive to aggregatory stimuli such as collagen, ADP, and thrombin. However, the resultant efficacy caused by activating AMPK was higher than that attributable to PPARγ stimulation. Similar results were obtained with pioglitazone. Taken together, rosiglitazone and pioglitazone inhibit platelet aggregation by activating AMPK. AMPK functions as a potential target of rosiglitazone and pioglitazone for their antiplatelet activity, although the in vivo or clinical relevance remains to be assessed.
authors.affiliation: College of Pharmacy, (Y.L., J.M.P., K.H.C., K.L., M.Y.L.), and Department of Laboratory Medicine, Dongguk University Ilsan Hospital (H.J.H.), Dongguk University, Seoul, South Korea.
authors.forename: Yingqiu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: College of Pharmacy, (Y.L., J.M.P., K.H.C., K.L., M.Y.L.), and Department of Laboratory Medicine, Dongguk University Ilsan Hospital (H.J.H.), Dongguk University, Seoul, South Korea.
authors.forename: Jung-Min
authors.initials: JM
authors.lastname: Park
authors.affiliation: College of Pharmacy, (Y.L., J.M.P., K.H.C., K.L., M.Y.L.), and Department of Laboratory Medicine, Dongguk University Ilsan Hospital (H.J.H.), Dongguk University, Seoul, South Korea.
authors.forename: Kyung-Hwa
authors.initials: KH
authors.lastname: Chang
authors.affiliation: College of Pharmacy, (Y.L., J.M.P., K.H.C., K.L., M.Y.L.), and Department of Laboratory Medicine, Dongguk University Ilsan Hospital (H.J.H.), Dongguk University, Seoul, South Korea.
authors.forename: Hee Jin
authors.initials: HJ
authors.lastname: Huh
authors.affiliation: College of Pharmacy, (Y.L., J.M.P., K.H.C., K.L., M.Y.L.), and Department of Laboratory Medicine, Dongguk University Ilsan Hospital (H.J.H.), Dongguk University, Seoul, South Korea.
authors.forename: Kyeong
authors.initials: K
authors.lastname: Lee
authors.affiliation: College of Pharmacy, (Y.L., J.M.P., K.H.C., K.L., M.Y.L.), and Department of Laboratory Medicine, Dongguk University Ilsan Hospital (H.J.H.), Dongguk University, Seoul, South Korea mlee@dongguk.edu.
authors.forename: Moo-Yeol
authors.initials: MY
authors.lastname: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000818:Animals; D008297:Male; D000077205:Pioglitazone; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D010975:Platelet Aggregation Inhibitors; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D055372:AMP-Activated Protein Kinases; D000077205:Pioglitazone