Endothelin-1 induces functionally active CD40 protein via nuclear factor-kappaB in human vascular smooth muscle cells.
A plethora of evidence supports a link between inflammation and atherogenesis. The vasoactive peptide endothelin-1 (ET-1) has both proatherogenic and proinflammatory properties. The CD40-CD154 signaling pathway exhibits a direct influence on atherogenesis. We therefore tested the hypothesis that ET-1 induces CD40 in human vascular smooth muscle cells (SMC). ET-1 concentration-dependently stimulated CD40 protein in SMC. The specific ET-A-receptor antagonist BQ-123 prevented CD40 induction demonstrating receptor specificity of the ET-1 effect. Experiments with PI-1, an inhibitor of the IkappaB-a-degrading proteasome complex, demonstrated involvement of the transcription factor NF-kappaB in ET-1-induced CD40 expression. Specific decoy oligodeoxynucleotides with the consensus binding sequence for NF-kappaB and AP-1 supported a NF-kappaB-dependent and AP-1-independent induction pathway. Functional relevance of ET-1-induced CD40 expression was demonstrated by an increase in IL-6 secretion after stimulation with CD154 of cells preactivated with ET-1. The data show a link between a proatherogenic vasoactive peptide and cell-cell contact mediated inflammatory pathways and may implicate novel therapeutic options for vascular disease.
Browatzki
M
M
Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
Pfeiffer
C A H
CA
Schmidt
J
J
Kranzhöfer
Roger
R
D000959:Antihypertensive Agents / Q000494:pharmacology; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000494:pharmacology; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D009841:Oligonucleotides / Q000737:chemistry / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000502:physiology; D012501:Saphenous Vein / Q000166:cytology / Q000601:surgery; D018808:Transcription Factor AP-1 / Q000378:metabolism
D000959:Antihypertensive Agents; D019013:CD40 Antigens; D016895:Culture Media, Serum-Free; D015853:Cysteine Proteinase Inhibitors; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D015850:Interleukin-6; D016328:NF-kappa B; D009841:Oligonucleotides; D009842:Oligopeptides; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D018808:Transcription Factor AP-1; C090535:benzyloxycarbonyl-isoleucyl-glutamyl(O-tert-butyl)-alanyl-leucinal; D023201:CD40 Ligand; C072247:cyclo(Trp-Asp-Pro-Val-Leu)