Endothelin-1 regulates proliferative responses, both alone and synergistically with PDGF, in rat tracheal smooth muscle cells.
The peptide, endothelin-1 (ET-1) regulates proliferative responses in numerous cell types. Recently, a dual ET receptor antagonist was shown to prevent the increase in airway smooth muscle cell (SMC) proliferation that accompanies airway smooth muscle remodeling in a rat model of experimental asthma. Thus, we used [(3)H]-thymidine incorporation assays and western immunoblotting to identify signaling pathways that regulate proliferative responses in cultured rat tracheal SMC. Our data indicate that ET-1 activation of the ET A receptor subtype induced [(3)H]-thymidine incorporation and activation of ERK 1/2 in primary rat tracheal SMC. ET-1-induced [(3)H]-thymidine incorporation and activation of ERK 1/2 were inhibited by pretreatment of SMC with pertussis toxin or down regulation of phorbol ester responsive isoforms of PKC. While ET- 1-induced ERK 1/2 activation was unaffected following inhibition of Rho kinase, ET-1-induced [(3)H]-thymidine incorporation was abrogated. ET-1 also potentiated [(3)H]-thymidine incorporation as well as cell proliferation of SMC stimulated with PDGF-BB and this response did not appear to be regulated by ERK1/ 2. These data demonstrate that ET-1 induces activation of multiple G proteins that regulate rat tracheal SMC proliferative responses, likely through signaling pathways downstream of ERK1/2 and Rho kinase.
Meakins-Christie Laboratories, Department of Medicine, McGill University, St. Urbain, Montreal, Quebec.
Linda
L
Yahiaoui
Annie
A
Villeneuve
Héctor
H
Valderrama-Carvajal
Fiona
F
Burke
Elizabeth D
ED
Fixman
D000818:Animals; D001249:Asthma / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D019332:Endothelin-1 / Q000008:administration & dosage / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008954:Models, Biological; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects*; D010982:Platelet-Derived Growth Factor / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D044022:Receptor, Endothelin A / Q000145:classification / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013936:Thymidine / Q000378:metabolism; D014132:Trachea / Q000166:cytology / Q000187:drug effects*
D019332:Endothelin-1; D010982:Platelet-Derived Growth Factor; D044022:Receptor, Endothelin A; D019204:GTP-Binding Proteins; D013936:Thymidine