Nitrovasodilators inhibit platelet-derived growth factor-induced proliferation and migration of activated human hepatic stellate cells.
OBJECTIVE
Nitrovasodilators have been proposed for the treatment of portal hypertension alone or in combination with beta-blockers. In addition to their vasodilatory properties, nitric oxide (NO) donors may exert direct antifibrogenic properties. We evaluated the effect of nitroglycerin (NTG) and S-nitroso-N-acetyl penicillamine (SNAP) on the mitogenic and chemotactic properties of platelet-derived growth factor (PDGF)-BB and the modulation of the relative intracellular signaling pathways in fully activated human hepatic stellate cells (HSCs), a cell type that plays an active role in liver fibrogenesis and portal hypertension.


RESULTS
Both NTG and SNAP induced a dose-dependent decrease in PDGF-induced DNA synthesis and cell migration, which was associated with a decrease in PDGF-induced intracellular Ca(2+) increase and extracellular signal-regulated kinase (ERK) activity. These effects were not related to activation of the classic soluble guanylate cyclase (sGC)/guanosine 3',5'-cyclic monophosphate pathway; accordingly, Western blot analysis of HSC lysates revealed the absence of the alpha(1)beta(1) ubiquitous subunits of sGC, whereas they were detectable in quiescent HSCs, freshly isolated from normal human liver. Conversely, both NTG and SNAP induced a more than 10-20-fold increase in prostaglandin E(2) in cell supernatants within 1 minute, associated with an increase in intracellular adenosine 3',5'-cyclic monophosphate levels. Accordingly, the inhibitory effects of NO donors on PDGF action and signaling were eliminated after preincubation with ibuprofen.


CONCLUSIONS
These results suggest that NO donors may exert a direct antifibrogenic action by inhibiting proliferation, motility, and contractility of HSCs in addition to a reduction of fibrillar extracellular matrix accumulation.
Dipartimento di Farmacologia Preclinica e Clinica, Italy.
P
P
Failli
R M
RM
DeFRANCO
A
A
Caligiuri
A
A
Gentilini
R G
RG
Romanelli
F
F
Marra
G
G
Batignani
C T
CT
Guerra
G
G
Laffi
P
P
Gentilini
M
M
Pinzani
D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D006490:Hemostatics / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000201:enzymology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D005996:Nitroglycerin / Q000494:pharmacology*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013917:Thrombin / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*
D006490:Hemostatics; D020030:Nitric Oxide Donors; D010982:Platelet-Derived Growth Factor; C110881:S-nitro-N-acetylpenicillamine; D014665:Vasodilator Agents; D010738:Type C Phospholipases; D013917:Thrombin; D006162:Guanylate Cyclase; D005996:Nitroglycerin; D010396:Penicillamine; D006152:Cyclic GMP; D015232:Dinoprostone; D002118:Calcium