title: Protection from apoptotic cell death by cilostazol, phosphodiesterase type III inhibitor, via cAMP-dependent protein kinase activation.
abstract: This study aimed to elucidate whether the effect of cilostazol to suppress apoptotic cell death is directly coupled to cAMP-dependent protein kinase activation in human umbilical vein endothelial cells (HUVECs). After exposure of HUVECs to LPS (1 microgml(-1)) for 18 h, the endothelial cells irregularly aggregated with loss of cobblestone appearance, which was reversed by cilostazol (1-100 microM), as well as by cilostamide (cilostazol analog), and cilostazol metabolites (OPC-13015 and OPC-31213), respectively. LPS-stimulated production of reactive oxygen species (ROS) was significantly reduced by cilostazol (0.1-10 microM). In line with these, LPS (1 microgml(-1))- and TNF-alpha (200 ngml(-1))-induced DNA fragmentation, assessed by agarose gel electrophoresis, was significantly reduced by treatment with cilostazol (10 microM) as well as by dibutyryl cAMP (100 microM). This effect was reversed by cAMP-dependent protein kinase inhibitor, Rp-cAMPs (200 microM). Further, LPS (1 microgml(-1))-induced decrease in Bcl-2 and increase in Bax protein expression were fully reversed by cilostazol (10 microM) and dibutyryl cAMP (100 microM), all of which were antagonized by Rp-cAMPs (200 microM). Taken together, cilostazol effectively protected HUVECs from LPS- and TNF-alpha-induced cell death associated with oligonucleosomal DNA fragmentation via activation of cAMP-dependent protein kinase.
authors.affiliation: Department of Pharmacology, College of Medicine, Pusan National University, 10 Ami-Dong 1-Ga, Seo-Gu, Busan, Republic of Korea.
authors.forename: Mi Jeong
authors.initials: MJ
authors.lastname: Kim
authors.forename: Jeong Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: So Youn
authors.initials: SY
authors.lastname: Park
authors.forename: Ki Whan
authors.initials: KW
authors.lastname: Hong
authors.forename: Chi Dae
authors.initials: CD
authors.lastname: Kim
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Kim
authors.forename: Won Suk
authors.initials: WS
authors.lastname: Lee
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D003994:Bucladesine / Q000494:pharmacology; D002460:Cell Line; D000077407:Cilostazol; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D053938:DNA Fragmentation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000648:ultrastructure; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D003994:Bucladesine; D017868:Cyclic AMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D000077407:Cilostazol