Endothelin 1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells.
OBJECTIVE
Endothelin (ET) 1 could be involved in the regulation of hepatic microcirculation and in the development of portal hypertension. The expression and distribution of ET-1 in normal and cirrhotic liver tissue and its effects on hepatic stellate cells (HSCs), liver-specific pericytes, were investigated.


METHODS
ET-1 expression in liver tissue was analyzed using in situ hybridization and immunohistochemistry. Secretion of ET-1 by HSC was evaluated by radioimmunoassay. Changes in intracellular Ca2+ concentration and cell contraction were studied using digital video imaging. Specific binding of ET-1 was evaluated using self- and cross-displacement curves.


RESULTS
ET-1 expression was markedly enhanced in cirrhotic liver tissue, where activated HSCs were shown to be major sites of ET-1 synthesis, as confirmed by studies performed on cultured human HSC. ET-1 exerted several biological actions on HSC, including mitogenicity, activation of mitogen-activated protein kinase, and a rapid increase in intracellular Ca2+ coupled with reversible cell contraction. All these effects appeared to be mediated by ETA receptors. Finally, the relative prevalence of ETA and ETB binding sites changed with the progressive phenotypical modulation of HSC.


CONCLUSIONS
ET-1 may act as a paracrine and autocrine factor for activated HSC and contribute to the increased resistance to portal flow in cirrhotic liver.
Pinzani
M
M
Istituto di Medicina Interna-Centro Interuniversitario di Fisiopatologia Epatica, Florence, Italy.
Milani
S
S
De Franco
R
R
Grappone
C
C
Caligiuri
A
A
Gentilini
A
A
Tosti-Guerra
C
C
Maggi
M
M
Failli
P
P
Ruocco
C
C
Gentilini
P
P
D017667:Adipocytes / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000704:Analysis of Variance; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division; D002478:Cells, Cultured; D016232:Endothelins / Q000378:metabolism* / Q000502:physiology; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011863:Radioimmunoassay; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism
D016232:Endothelins; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D002118:Calcium