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Biological effects of C-type natriuretic peptide in human myofibroblastic hepatic stellate cells
Insights
C-type natriuretic peptide (CNP) inhibits human myofibroblastic hepatic stellate cells (mHSC) proliferation and contraction by activating natriuretic peptide receptor-B (NPR-B). This suggests CNP may counteract liver fibrogenesis and portal hypertension in chronic liver diseases.
Area of Science:
- Hepatology
- Cell Biology
- Cardiovascular Physiology
Background:
- Chronic liver diseases involve hepatic stellate cells (HSC) activating into a myofibroblastic phenotype (mHSC).
- mHSC proliferation and contraction contribute to liver fibrosis and portal hypertension.
- The role of natriuretic peptides in HSC function was previously unknown.
Purpose of the Study:
- To investigate the expression and function of natriuretic peptide receptors (NPR) in human mHSC.
- To determine the effects of C-type natriuretic peptide (CNP) on mHSC proliferation and contraction.
Main Methods:
- Identified NPR-B mRNA in human mHSC via RT-PCR.
- Assessed NPR-B functionality using binding studies and cGMP level measurements.
- Evaluated CNP's impact on mHSC proliferation and contraction using specific inhibitors and analogs.
- Analyzed downstream signaling pathways including ERK, JNK, and AP-1 DNA binding.
- Investigated CNP's effect on calcium influx and store-operated calcium channels.
Main Results:
- Human mHSC express functional NPR-B, responding to CNP with increased cGMP.
- CNP significantly inhibited mHSC proliferation and contraction.
- Inhibition of proliferation involved reduced ERK, JNK, and AP-1 activation.
- CNP-induced relaxation was mediated by blocking calcium influx through store-operated channels.
Conclusions:
- This study provides the first evidence of a hepatic effect of CNP, targeting human mHSC.
- Activation of NPR-B by CNP in mHSC inhibits both cell growth and contraction.
- CNP represents a potential therapeutic agent against liver fibrogenesis and portal hypertension in chronic liver diseases.
Abstract:
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.