Biological effects of C-type natriuretic peptide in human myofibroblastic hepatic stellate cells.
During chronic liver diseases, hepatic stellate cells (HSC) acquire a myofibroblastic phenotype, proliferate, and synthetize fibrosis components. Myofibroblastic HSC (mHSC) also participate to the regulation of intrahepatic blood flow, because of their contractile properties. Here, we examined whether human mHSC express natriuretic peptide receptors (NPR). Only NPR-B mRNA was identified, which was functional as demonstrated in binding studies and by increased cGMP levels in response to C-type natriuretic peptide (CNP). CNP inhibited mHSC proliferation, an effect blocked by the protein kinase G inhibitor 8-(4 chlorophenylthio)-cGMP and by the NPR antagonist HS-142-1 and reproduced by analogs of cGMP. Growth inhibition was associated with a reduction of extracellular signal-regulated kinase and c-Jun N-terminal kinase and with a blockade of AP-1 DNA binding. CNP and cGMP analogs also blunted mHSC contraction elicited by thrombin, by suppressing calcium influx. The relaxing properties of CNP were mediated by a blockade of store-operated calcium channels, as demonstrated using a calcium-free/calcium readdition protocol. These results constitute the first evidence for a hepatic effect of CNP and identify mHSC as a target cell. Activation of NPR-B by CNP in human mHSC leads to inhibition of both growth and contraction. These data suggest that during chronic liver diseases, CNP may counteract both liver fibrogenesis and associated portal hypertension.
Tao
J
J
Unité INSERM 99, Hôpital Henri Mondor, AP-HP, 94010 Créteil, France.
Mallat
A
A
Gallois
C
C
Belmadani
S
S
Méry
P F
PF
Nhieu
J T
JT
Pavoine
C
C
Lotersztajn
S
S
D017667:Adipocytes / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000502:physiology; D004247:DNA / Q000378:metabolism; D006162:Guanylate Cyclase / Q000032:analysis / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008103:Liver Cirrhosis / Q000188:drug therapy; D048670:MAP Kinase Kinase 4; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D020098:Natriuretic Peptide, C-Type / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors; D017461:Receptors, Atrial Natriuretic Factor / Q000032:analysis / Q000187:drug effects; D013917:Thrombin / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D018808:Transcription Factor AP-1; D020098:Natriuretic Peptide, C-Type; D004247:DNA; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D013917:Thrombin; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C073616:atrial natriuretic factor receptor C; D006152:Cyclic GMP; D002118:Calcium