P. Failli et al., Nitrovasodilators inhibit platelet-derived growth factor-induced proliferation and migration of activated human hepatic stellate cells, GASTROENTY, 119(2), 2000, pp. 479-492
Background & Aims: Nitrovasodilators have been proposed for the treatment o
f portal hypertension alone or in combination with beta-blockers. In additi
on to their vasodilatory properties, nitric oxide (NO) donors may exert dir
ect antifibrogenic properties. We evaluated the effect of nitroglycerin (NT
G) and S-nitroso-N-acetyl penicillamine (SNAP) on the mitogenic and chemota
ctic properties of platelet-derived growth factor (PDGF)BB and the modulati
on of the relative intracellular signaling pathways in fully activated huma
n hepatic stellate cells (HSCs), a cell type that plays an active role in l
iver fibrogenesis and portal hypertension. Methods Br Results: Both NTG and
SNAP induced a dose-dependent decrease in PDGF-induced DNA synthesis and c
ell migration, which was associated with a decrease in PDGF-induced intrace
llular Ca2+ increase and extracellular signal-regulated kinase (ERK) activi
ty. These effects were not related to activation of the classic soluble gua
nylate cyclase (sGC)/guanosine 3',5'-cyclic monophosphate pathway; accordin
gly, Western blot analysis of HSC lysates revealed the absence of the alpha
(1)beta(1) ubiquitous subunits of sGC, whereas they were detectable in quie
scent 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 ce
ll supernatants within 1 minute, associated with an increase in intracellul
ar adenosine 3',5'-cyclic monophosphate levels. Accordingly, the inhibitory
effects of NO donors on PDGF action and signaling were eliminated after pr
eincubation with ibuprofen, Conclusions: These results suggest that NO dono
rs may exert a direct antifibrogenic action by inhibiting proliferation, mo
tility, and contractility of HSCs in addition to a reduction of fibrillar e
xtracellular matrix accumulation.