Urotensin II promotes the production of LTC4 in rat aortic adventitial fibroblasts through NF-κB-5-LO pathway by p38 MAPK and ERK activations.
Adventitia is the outer part of the arterial wall where the inflammatory response often occurs. Urotensin II (UII) is a potent vasoconstrictive peptide that also promotes the inflammatory process in patients with cardiovascular disease. Leukotriene C4 (LTC4), a lipid mediator, was recently found to play a role in the inflammatory process in the artery. We hypothesized that the adventitia is one of the resources of LTC4 and that UII may promote LTC4 production through the 5-LO (5-lipoxygenase) pathway in adventitial fibroblasts. Rat adventitial fibroblasts were isolated and incubated in serum-free medium with either UII alone or in combination with inhibitors of p38 MAPK, ERK, and UII receptors. The expression of 5-LO was detected using real-time polymerase chain reaction and Western blot. The translocation and binding activity of nuclear factor (NF)-κB were measured using immunofluorescence and electrophoretic mobility shift assay, respectively. The production of LTC4 was measured by enzyme-linked immunosorbent assay. The results indicated that: (1) adventitial fibroblasts were a source of LTC4 production; (2) UII increased the expression of the 5-LO mRNA and the protein by NF-κB activation through p38 MAPK and ERK pathways; and (3) UII promoted the LTC4 release in fibroblasts through the 5-LO pathway by p38 MAPK and ERK activations. The 5-LO pathway mediates LTC4 production, which may be a new mechanism in the pathogenesis of the vascular adventitial inflammation caused by UII.
Division of Cardiology, Department of Internal Medicine, Peking University First Hospital, Xishikudajie #8, West District, Beijing, 10034, People's Republic of China.
Xiao
X
Dong
Xiaojin
X
Ye
Nana
N
Song
Jing
J
Zhao
Beibing
B
Di
Fen
F
Peng
Chaoshu
C
Tang
Wenhui
W
Ding
D021581:Active Transport, Cell Nucleus; D063194:Adventitia / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology; D018836:Inflammation Mediators / Q000378:metabolism*; D017997:Leukotriene C4 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014579:Urotensins / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D018836:Inflammation Mediators; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D014579:Urotensins; C473142:Uts2r protein, rat; D017997:Leukotriene C4; C029677:urotensin II; D001094:Arachidonate 5-Lipoxygenase; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases