Biological effects of C-type natriuretic peptide in human myofibroblastic hepatic stellate cells

During chronic liver diseases, hepatic stellate cells (HSC) acquire a myofi broblastic phenotype, proliferate, and synthetize fibrosis components. Myof ibroblastic HSC (mHSC) also participate to the regulation of intrahepatic b lood flow, because of their contractile properties. Here, we examined wheth er 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 MS-142-1 a nd reproduced by analogs of cGMP. Growth inhibition was associated with a r eduction of extracellular signal-regulated kinase and c-Jun N-terminal kina se and with a blockade of AP-1 DNA binding. CNP and cGMP analogs also blunt ed mHSC contraction elicited by thrombin, by suppressing calcium influx. Th e relaxing properties of CNP were mediated by a blockade of store-operated calcium channels, as demonstrated using a calcium-free/calcium readdition p rotocol. These results constitute the first evidence for a hepatic effect o f CMP and identify mHSC as a target cell. Activation of NPR-B by CNP in hum an mHSC leads to inhibition of both growth and contraction. These data sugg est that during chronic liver diseases, CNP may counteract both liver fibro genesis and associated portal hypertension.