title: Endothelin-1 stimulates small artery VCAM-1 expression through p38MAPK-dependent neutral sphingomyelinase.
abstract: Endothelin-1 (ET-1) stimulates vascular cell adhesion molecule (VCAM-1) expression, a process associated with arterial remodelling. However, the pathways activated by ET-1 that lead to VCAM-1 expression are not fully understood. It is reported that sphingomyelinases are necessary for VCAM-1 expression in response to cytokines. Our aim was to investigate the role of sphingomyelinases in ET-1-induced VCAM-1 expression. Acid and neutral sphingomyelinase activities were measured in extracts from rat mesenteric small arteries (RMSA). ET-1 (1-100 nmol/l) stimulated neutral but not acid sphingomyelinase. The activation was rapid, peaking within 5 min and transient, returning towards baseline by 10 min and inhibited by BQ-788, GW4869 and SB203580, which are inhibitors of ET(B) receptor, neutral sphingomyelinase and p38MAPK, respectively. Both GW4869 and SB203580 are reported to inhibit activation of neutral sphingomyelinase 2 implicating it in the response to ET-1. Accordingly we investigated the expression of this isoform and found it was present in RMSA, predominantly in endothelial cells. Treatment of RMSA with ET-1 (1-100 nmol/l) for 16 h increased VCAM-1 expression, which was inhibited by GW4869 and SB203580. These results indicate that ET-1 stimulates arterial VCAM-1 expression through p38MAPK-dependent activation of neutral sphingomyelinases. This suggests a role for sphingolipids in ET-1-induced vascular inflammation in cardiovascular disease.
authors.affiliation: Cardiovascular Medicine, University of Manchester, Manchester, UK. johanian@manchester.ac.uk
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ohanian
authors.forename: Simon P
authors.initials: SP
authors.lastname: Forman
authors.forename: Gideon
authors.initials: G
authors.lastname: Katzenberg
authors.forename: Vasken
authors.initials: V
authors.lastname: Ohanian
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology / Q000502:physiology*; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D008638:Mesenteric Arteries / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D000814:Aniline Compounds; D001597:Benzylidene Compounds; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; C468773:GW 4869; D055551:HSP27 Heat-Shock Proteins; D007093:Imidazoles; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D011725:Pyridines; C465539:SB202494; D019010:Vascular Cell Adhesion Molecule-1; C086539:BQ 788; D048051:p38 Mitogen-Activated Protein Kinases; C107180:Smpd3 protein, rat; D013108:Sphingomyelin Phosphodiesterase; C093642:SB 203580; C072247:cyclo(Trp-Asp-Pro-Val-Leu)