Oxidative stress plays an essential role in
liver fibrosis. This study investigated whether
MitoQ, an orally active mitochondrial
antioxidant, decreases
liver fibrosis. Mice were injected with
corn oil or
carbon tetrachloride (CCl4, 1:3 dilution in
corn oil; 1 µl/g, ip) once every 3 days for up to 6 weeks.
4-Hydroxynonenal adducts increased markedly after CCl4 treatment, indicating oxidative stress.
MitoQ attenuated oxidative stress after CCl4.
Collagen 1α1
mRNA and
hydroxyproline increased markedly after CCl4 treatment, indicating increased
collagen formation and deposition. CCl4 caused overt pericentral
fibrosis as revealed by both the sirius red staining and second harmonic generation microscopy.
MitoQ blunted
fibrosis after CCl4. Profibrotic transforming growth factor-β1 (TGF-β1)
mRNA and expression of smooth muscle α-actin, an
indicator of hepatic stellate cell (HSC) activation, increased markedly after CCl4 treatment. Smad 2/3, the major mediator of TGF-β fibrogenic effects, was also activated after CCl4 treatment.
MitoQ blunted HSC activation, TGF-β expression, and Smad2/3 activation after CCl4 treatment.
MitoQ also decreased
necrosis, apoptosis and
inflammation after CCl4 treatment. In cultured HSCs,
MitoQ decreased oxidative stress, inhibited HSC activation, TGF-β1 expression, Smad2/3 activation, and extracellular signal-regulated
protein kinase activation. Taken together, these data indicate that mitochondrial
reactive oxygen species play an important role in
liver fibrosis and that mitochondria-targeted
antioxidants are promising potential
therapies for prevention and treatment of
liver fibrosis.