Profibrotic effects of endothelin-1 via the ETA receptor in cultured human cardiac fibroblasts.
OBJECTIVE
Endothelin-1 (ET-1) has been implicated in pathologic remodelling and tissue repair processes in the heart. We investigated the effects of ET-1 on growth and collagen synthesis responses in cardiac fibroblasts isolated from human hearts. We also studied the receptor subtype(s) mediating such responses and the factors regulating their expression.


METHODS
Fibroblasts were isolated from cardiac transplant recipient hearts and characterised by immunocytochemistry. Serum-starved cells were exposed to ET-1 and incorporation of [3H]proline and thymidine were measured as indexes of collagen and DNA synthesis respectively. Blocking experiments utilised the selective ETA receptor antagonist BQ123 and the ETB antagonist BQ788.


RESULTS
ET-1 elicited a potent collagen synthesis response in cardiac fibroblasts, with a maximum 29+/-5% increase that was abolished by BQ123. Cardiac fibroblasts responded to ET-1 with a concentration-dependent decrease in DNA synthesis rate. The effects of ET-1 were similar to those of TGF-beta. Radioligand binding studies revealed the presence of high-affinity ET-1 binding sites on these cells, which were upregulated by treatment with the growth factors PDGF and EGF but downregulated by TGF-beta.


CONCLUSIONS
These results therefore implicate ET-1 as a trophic agent in the human heart with the ability to influence the development of cardiac fibrosis.
Hafizi
Sassan
S
Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College School of Medicine at Harefield Hospital, Middlesex. sassan.hafizi@klkemi.mas.lu.se
Wharton
John
J
Chester
Adrian H
AH
Yacoub
Magdi H
MH
D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D005355:Fibrosis; D006801:Humans; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D044022:Receptor, Endothelin A / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D010982:Platelet-Derived Growth Factor; D044022:Receptor, Endothelin A; D016212:Transforming Growth Factor beta; C086539:BQ 788; D004815:Epidermal Growth Factor; D003094:Collagen; D004247:DNA; C072247:cyclo(Trp-Asp-Pro-Val-Leu)