title: The antiplatelet activity of magnolol is mediated by PPAR-β/γ.
abstract: Activation of peroxisome proliferator-activated receptor (PPAR) isoforms (α, β/δ, and γ) is known to inhibit platelet aggregation. In the present study, we examined whether PPARs-mediated pathways contribute to the antiplatelet activity of magnolol, a compound purified from Magnolia officinalis. Magnolol (20-60 μM) dose-dependently enhanced the activity and intracellular level of PPAR-β/γ in platelets. In the presence of selective PPAR-β antagonist (GSK0660) or PPAR-γ antagonist (GW9662), the inhibition of magnolol on collagen-induced platelet aggregation and intracellular Ca(2+) mobilization was significantly reversed. Moreover, magnolol-mediated up-regulation of NO/cyclic GMP/PKG pathway and Akt phosphorylation leading to increase of eNOS activity were markedly abolished by blocking PPAR-β/γ activity. Additionally, magnolol significantly inhibited collagen-induced PKCα activation through a PPAR-β/γ and PKCα interaction manner. The arachidonic acid (AA) or collagen-induced thromboxane B(2) formation and elevation of COX-1 activity caused by AA were also markedly attenuated by magnolol. However, these above effects of magnolol on platelet responses were strongly reduced by simultaneous addition of GSK0660 or GW9662, suggesting that PPAR-β/γ-mediated processes may account for magnolol-regulated antiplatelet mechanisms. Similarly, administration of PPAR-β/γ antagonists remarkably abolished the actions of magnolol in preventing platelet plug formation and prolonging bleeding time in mice. Taken together, we demonstrate for the first time that the antiplatelet and anti-thrombotic activities of magnolol are modulated by up-regulation of PPAR-β/γ-dependent pathways.
authors: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors: Ching-Yu
authors: CY
authors: Shih
authors: Tz-Chong
authors: TC
authors: Chou
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000096:biosynthesis; D017869:Cyclic GMP-Dependent Protein Kinases / Q000097:blood; D051545:Cyclooxygenase 1 / Q000097:blood; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000097:blood; D017705:Lignans / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000097:blood; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000097:blood; D048068:PPAR-beta / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000097:blood; D010766:Phosphorylation; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051571:Protein Kinase C-alpha / Q000097:blood; D051057:Proto-Oncogene Proteins c-akt / Q000097:blood; D011817:Rabbits; D018160:Receptors, Cytoplasmic and Nuclear / Q000097:blood; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase; D013929:Thromboxane B2 / Q000097:blood; D015854:Up-Regulation
chemical_list: D001713:Biphenyl Compounds; D005343:Fibrinolytic Agents; D017705:Lignans; D047495:PPAR gamma; D048068:PPAR-beta; D010975:Platelet Aggregation Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; C005498:magnolol; D009569:Nitric Oxide; D013929:Thromboxane B2; D052250:Nitric Oxide Synthase Type III; D051545:Cyclooxygenase 1; D051057:Proto-Oncogene Proteins c-akt; D017869:Cyclic GMP-Dependent Protein Kinases; D051571:Protein Kinase C-alpha; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; D002118:Calcium