title: Mechanisms of andrographolide-induced platelet apoptosis in human platelets: regulatory roles of the extrinsic apoptotic pathway.
abstract: Andrographolide, a novel nuclear factor-κB (NF-κB) inhibitor, is isolated from the leaves of Andrographis paniculata. Platelet activation is relevant to a variety of coronary heart diseases. Our recent studies revealed that andrographolide possesses potent antiplatelet activity by inhibition of the p38 MAPK/(●) HO-NF-κB-ERK2 cascade. Although platelets are anucleated cells, apoptotic machinery apparatus recently has been found to regulate platelet activation and limit platelet lifespan. Therefore, we further investigated the regulatory effects of andrographolide on platelet apoptotic events. In this study, apoptotic signaling events for caspase-3, -8, and Bid were time (10-60 min)- and dose (25-100 μΜ)-dependently activated by andrographolide in human platelets. Andrographolide could also disrupt mitrochondrial membrane potential. In addition, caspase-8 inhibitor (z-IETD-fmk, 50 μΜ) was found to reverse andrographolide-induced caspase-8 activation, whereas the antagonistic anti-Fas receptor (ZB4, 500 ng/mL) and anti-tumor necrosis factor-R1 (H398, 10 µg/mL) monoclonal antibodies did not. In conclusion, this study for the first time demonstrated that andrographolide might limit platelet lifespan by initiating the caspase-8-dependent extrinsic apoptotic pathway, in spite of no direct evidence that death receptors are involved in this process proved. Overall, the various medicinal properties of andrographolide suggest its potential value in treating patients with thromboembolic disorders.
authors.affiliation: Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan; Department of Neurology, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Lien
authors.forename: Cheng-Chen
authors.initials: CC
authors.lastname: Su
authors.forename: Wen-Hsien
authors.initials: WH
authors.lastname: Hsu
authors.forename: Wan-Jung
authors.initials: WJ
authors.lastname: Lu
authors.forename: Chi-Li
authors.initials: CL
authors.lastname: Chung
authors.forename: Ting-Lin
authors.initials: TL
authors.lastname: Yen
authors.forename: Hou-Chang
authors.initials: HC
authors.lastname: Chiu
authors.forename: Joen-Rong
authors.initials: JR
authors.lastname: Sheu
authors.forename: Kuan-Hung
authors.initials: KH
authors.lastname: Lin
mesh_terms: D035685:Andrographis / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D018515:Plant Leaves / Q000737:chemistry; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D004224:Diterpenes; C030419:andrographolide; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8
keywords: Bid; andrographolide; caspase-3; caspase-8; mitochondrial membrane potential; platelets