title: Blockade of phosphodiesterase-III protects against oxygen-glucose deprivation in endothelial cells by upregulation of VE-cadherin.
abstract: We recently reported that a phosphodiesterase-III inhibitor, cilostazol, prevented the hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tissue plasminogen activator (tPA) and that it reversed tPA-induced cell damage by protecting the neurovascular unit, particularly endothelial cells. However, the mechanisms of cilostazol action are still not clearly defined. The adheren junction (AJ) protein, VE-cadherin, is a known mediator of endothelial barrier sealing and maintenance. Therefore, we tested whether cilostazol might promote expression of adhesion molecules in endothelial cells, thereby preventing deterioration of endothelial barrier functions. Human brain microvascular endothelial cells were exposed to 6-h oxygen-glucose deprivation (OGD). We compared cilostazol with aspirin treatments and examined 2 representative AJ proteins: VE-cadherin and platelet endothelial cell adhesion molecule-1 (PECAM-1). A protein kinase A (PKA) inhibitor, LY294002 (a PI3-K inhibitor), db-cAMP, and RP-cAMPS were used to assess the roles of cAMP, PKA, and PI3-K signaling, respectively, in cilostazol-induced responses. Cilostazol and db-cAMP prevented OGD-stress injury in endothelial cells by promoting VE-cadherin expression, but not PECAM-1. Aspirin did not prevent cell damage. P13-K inhibition by LY294002 had no influence on the effects of cilostazol, but inhibition of cAMP/PKA with PKA inhibitor and Rp-cAMPS suppressed cilostazol-induced inhibition of cell damage and promotion of VE-cadherin expression. In contrast, OGD stress had no detectable effects on VEGF, VEGF receptor, or angiopoietin-1 levels. Cilostazol promotes VE-cadherin expression through cAMP/PKA-dependent pathways in brain endothelial cells; thus, cilostazol effects on adhesion molecule signaling may provide protection against OGD stress in endothelial cells.
authors: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors: Mitsunori
authors: M
authors: Ishiguro
authors: Yukiya
authors: Y
authors: Suzuki
authors: Keisuke
authors: K
authors: Mishiro
authors: Mamoru
authors: M
authors: Kakino
authors: Kazuhiro
authors: K
authors: Tsuruma
authors: Masamitsu
authors: M
authors: Shimazawa
authors: Shinichi
authors: S
authors: Yoshimura
authors: Toru
authors: T
authors: Iwama
authors: Hideaki
authors: H
authors: Hara
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis* / Q000502:physiology; D015820:Cadherins / Q000096:biosynthesis* / Q000502:physiology; D002460:Cell Line; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism*; D019610:Cytoprotection / Q000187:drug effects* / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000172:deficiency*; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D010100:Oxygen / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D015854:Up-Regulation / Q000502:physiology; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D005947:Glucose; D010100:Oxygen; D010726:Phosphodiesterase Inhibitors; D000099152:Cadherin 5