title: Downregulation of BDNF Expression by PKC and by TNF-α in Human Endothelial Cells.
abstract: Brain-derived neurotrophic factor (BDNF) is a neurotrophin best characterized for its survival and differentiative effects on neurons. Recent studies demonstrated that BDNF and its receptors are also expressed in the peripheral vasculature, where it stimulates angiogenesis and promotes the survival of endothelial cells. This study was designed to investigate the angiogenic effects of BDNF and its expressional regulation by tumor necrosis factor (TNF-α) and protein kinase C (PKC) in endothelial cells. In the Matrigel angiogenesis assay, BDNF-stimulated vascular tube formation of human umbilical vein endothelial cells (HUVEC) was completely blocked by an inhibition of the TrkB receptor, but only partially inhibited by the inhibition of the p75(NTR) signaling. Treatment of HUVEC and HUVEC-derived EA.hy 926 cells with TNF-α resulted in a downregulation of BDNF expression, which could be prevented by the TNFR1 antagonist WP9QY. BDNF downregulation by TNF-α was associated with decreased angiogenic activity of HUVEC. The effect of TNF-α on BDNF expression could not be abolished by the inhibition of PKC. Treatment of HUVEC and EA.hy 926 cells with PKC-activating phorbol esters (phorbol-12-myristate-13-acetate, PMA or phorbol-12,13-dibutyrate) resulted in a downregulation of BDNF expression, whereas the inactive 4α-phorbol-12,13-didecanoate was without effect. PMA had no significant effect on BDNF mRNA stability and the downregulation of BDNF mRNA expression by PKC activation was likely a transcriptional event. BDNF downregulation by PMA could be prevented by PKC inhibitors Gö 6983 and rottlerin, but not by Gö 6976. Thus, a Gö 6983/rottlerin-sensitive PKC isoform is likely to be responsible for PMA-induced BDNF downregulation.
authors.affiliation: Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.forename: Petra
authors.initials: P
authors.lastname: Czerwinski
authors.forename: Ning
authors.initials: N
authors.lastname: Xia
authors.forename: Ulrich
authors.initials: U
authors.lastname: Förstermann
authors.forename: Huige
authors.initials: H
authors.lastname: Li
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors; D010456:Peptides, Cyclic / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020813:Receptor, trkB / Q000037:antagonists & inhibitors; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C465664:2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide; D000098:Acetophenones; D001578:Benzopyrans; D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D007211:Indoles; D008301:Maleimides; C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D010456:Peptides, Cyclic; D010703:Phorbol Esters; D017475:Receptors, Nerve Growth Factor; D014409:Tumor Necrosis Factor-alpha; C501648:WP9QY peptide; C081021:Go 6976; C579455:BDNF protein, human; C085746:rottlerin; D020813:Receptor, trkB; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate