Role of endothelin receptors on basal and endothelin-1-stimulated lung myofibroblast proliferation.
Proliferation of myofibroblasts (MYF) contributes to numerous lung disorders. Endothelin-1 (ET-1) production is increased in various lung diseases and could contribute to lung remodelling. The respective roles of ETA and ETB receptors (ETA-R, ETB-R) and the role of endogenous ET-1 production by lung MYF on proliferation of MYF remain uncertain. Rat lung MYF were isolated and 3H-thymidine and 3H-leucine incorporation assays were completed in the presence of a selective ETA-R antagonist, a selective ETB-R antagonist, or a combination of both. Receptor expression was evaluated by confocal imaging, and ET-1 levels were measured by ELISA. Confocal microscopy revealed abundant ETA-R and ETB-R expression on lung MYF. ET-1 (10 nmol/L) stimulated MYF proliferation and protein synthesis through PI3-kinase and p38 pathways. Although neither selective ETA-R blockade (BQ-123, 1 micromol/L) nor selective ETB-R blockade (BQ-788, 1 micromol/L) alone inhibited proliferation or protein synthesis, their combination almost completely abolished ET-1 mitogenic effect. Surprisingly, basal MYF proliferation was increased by selective blockade of either ETA-R or ETB-R alone, but not by dual blockade. ET-1 levels were not affected by the antagonists. Our findings indicate that both the ETA-R and the ETB-R regulate basal and stimulated lung MYF proliferation and suggest possible interactions between the receptors.
Research Centre, Montreal Heart Institute and Université de Montréal, Montreal, QC H1T1C8, Canada.
Annick
A
Préfontaine
Angelino
A
Calderone
Jocelyn
J
Dupuis
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D008168:Lung / Q000166:cytology* / Q000187:drug effects; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D032390:Myoblasts, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000502:physiology*; D044023:Receptor, Endothelin B / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D002867:Chromones; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009025:Morpholines; D009842:Oligopeptides; D010456:Peptides, Cyclic; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D011725:Pyridines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C086539:BQ 788; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C072247:cyclo(Trp-Asp-Pro-Val-Leu)