title: Possible roles of neuropeptide Y Y3-receptor subtype in rat aortic endothelial cell proliferation under hypoxia, and its specific signal transduction.
abstract: The present study was undertaken to determine whether neuropeptide Y (NPY) induces proliferation of rat aortic endothelial cells (RAECs). Since NPY increased the permeability of RAEC monolayers to large molecules via the NPY Y(3) receptor, RAEC proliferation has been evaluated in terms of NPY-receptor subtypes and also intracellular mechanisms. RAECs were incubated with gases containing 20, 15, or 10% O(2) and a certain amount of N(2), depending on the O(2) content in 5% CO(2) incubators. NPY (10(-9)-10(-6) M) increased the RAEC numbers under hypoxic conditions, such as 15 or 10% O(2). Peptide YY elicited no proliferative effect on RAEC, and NPY-(18-36) inhibited the NPY-induced increase in cell number, suggesting that NPY increases the RAEC count through the NPY Y(3) receptor. Pertussis toxin, U-73122, GF-109203X, myristorylated autocamtide-2-related inhibitory peptide, and wortmannin inhibited the NPY-induced proliferation of RAEC concentration dependently. DY9760e little affected the proliferation caused by NPY. ML-9 and imatinib actually enhanced the NPY-induced proliferation of cells. These results indicated that the NPY Y(3) receptor is coupled with G(i) protein, and that NPY-induced increases in RAEC proliferation are mediated by phospholipase C-protein kinase C and/or phosphatidylinositol 3-kinase pathways. In intracellular Ca(2+)-calmodulin-dependent pathways, calmodulin-dependent protein kinase II partly participates in the NPY-induced cell proliferation. Regarding the previously reported effect of NPY on the permeability of RAEC monolayers to large molecules, it is probable that protein kinase C and phosphatidylinositol 3-kinase pathways are activated for both permeability and cell proliferation induced by NPY under hypoxia, relevant to new insights into the roles of NPY in ischemia-hypoxia.
authors.affiliation: Department of Pharmacology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Chen
authors.forename: Guo-Gang
authors.initials: GG
authors.lastname: Feng
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Nishiwaki
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shimada
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Toru
authors.initials: T
authors.lastname: Komatsu
authors.forename: Naohisa
authors.initials: N
authors.lastname: Ishikawa
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia; D002463:Cell Membrane Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D008297:Male; D009478:Neuropeptide Y / Q000378:metabolism* / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D019894:Peptide YY / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018013:Receptors, Neuropeptide / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D002147:Calmodulin; D004791:Enzyme Inhibitors; D009478:Neuropeptide Y; D010446:Peptide Fragments; D018013:Receptors, Neuropeptide; C106657:neuropeptide Y3 receptor; D019894:Peptide YY; C059889:neuropeptide Y (18-36); D019869:Phosphatidylinositol 3-Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010738:Type C Phospholipases; C505410:Casp3 protein, rat; D053148:Caspase 3; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D002118:Calcium