title: ANP inhibits TNF-alpha-induced endothelial MCP-1 expression--involvement of p38 MAPK and MKP-1.
abstract: Atrial natriuretic peptide (ANP) has been shown to reduce tumor necrosis factor-alpha (TNF-alpha)-induced activation of endothelial cells via inhibition of p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappaB pathways. The aim of this study was to determine whether ANP is able to inhibit TNF-alpha-induced expression of monocyte chemoattractant protein-1 (MCP-1) in endothelial cells and to elucidate the mechanisms involved. Pretreatment of human umbilical vein endothelial cells (HUVEC) with ANP significantly reduced TNF-alpha-induced expression of MCP-1 protein and mRNA. The effects of ANP were shown to be mediated via the guanylyl-cyclase (GC)-coupled A receptor. Activation of the other GC-coupled receptor (natriuretic peptide receptor-B) by the C-type natriuretic peptide as well as activation of soluble GC with S-nitroso-L-glutathione (GSNO) exerted similar effects as ANP, supporting a role for cyclic guanosine monophosphate (cGMP) in the signal transduction. Antisense experiments showed a requirement of MAPK phosphatase-1 (MKP-1) induction and therefore, inhibition of p38 MAPK in the ANP-mediated inhibition of TNF-alpha-induced expression of MCP-1. To investigate a potential interplay between TNF-alpha-induced activation of p38 MAPK and NF-kappaB, the p38 MAPK inhibitor SB203580 and a dominant-negative p38 MAPK mutant were used. The results indicated that the blockade of p38 MAPK activity leads to an increased activation of NF-kappaB and therefore, suggest a counter-regulatory action of p38 MAPK and NF-kappaB. As antisense experiments revealed a pivotal role for MKP-1 induction and therefore, p38 MAPK inhibition in ANP-mediated attenuation of MCP-1 expression, this action seems to be rather independent of NF-kappaB inhibition.
authors.affiliation: Department of Pharmacy, University of Munich, Germany.
authors.forename: Nina C
authors.initials: NC
authors.lastname: Weber
authors.forename: Signe B
authors.initials: SB
authors.lastname: Blumenthal
authors.forename: Thomas
authors.initials: T
authors.lastname: Hartung
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
authors.forename: Alexandra K
authors.initials: AK
authors.lastname: Kiemer
mesh_terms: D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics*; D054638:Dual Specificity Phosphatase 1; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism; D006706:Homeostasis; D007093:Imidazoles / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface / Q000502:physiology; D026422:S-Nitrosoglutathione / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014471:Umbilical Veins; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D018797:Cell Cycle Proteins; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D007093:Imidazoles; D017874:Immediate-Early Proteins; D016328:NF-kappa B; D020030:Nitric Oxide Donors; D011725:Pyridines; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D026422:S-Nitrosoglutathione; D009320:Atrial Natriuretic Factor; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases; D006162:Guanylate Cyclase; C093642:SB 203580