In response to liver injury, HSCs undergo an activation process and transform into myofibroblast-like cells, a process characterized by loss of vitamin A and expression of α-smooth muscle actin (α-SMA).3, 4 Activated HSCs promote collagen synthesis and secretion. In addition, these cells produce a number of cytokines such as transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF), which play important roles in the development of liver fibrosis.5, 6 The involvement of reactive oxygen species (ROS) in liver fibrogenesis

has been documented. The activation and expression of various mediators are regulated by ROS by way of the redox-sensitive protein kinases and transcription Imatinib factors in HSCs.7, 8 Recently, nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase, originally identified

as a major source of ROS in phagocytes, was shown to play a key role in cellular signaling. NOX is a catalytic subunit of NADPH oxidase, a multisubunit enzyme composed of membrane-bound NOX and p22phox, associated with several cytosolic regulatory learn more subunits including p47phox. In recent years, several isoforms of NOX have been identified.9 NOX2 (gp91phox) is the phagocytic form of NOX, whereas NOX1 is a newly identified form that has been implicated in the pathogenesis of hypertension and inflammatory pain.10, 11 Previously, it was reported that mice lacking p47phox, a cytosolic subunit of NADPH oxidase, demonstrated reduced liver injury and fibrosis after bile duct ligation (BDL).12 In transgenic mice overexpressing Rac1, another cytosolic subunit necessary for enzyme activation, greater numbers of activated HSCs, increased liver damage, tuclazepam and fibrosis were demonstrated following treatment with

carbon tetrachloride (CCl4).13 In line with these findings, reduced liver fibrosis was demonstrated in mice lacking NOX2 treated with CCl4.14 Furthermore, NOX2 was recently shown to play a key role in activation of HSCs following phagocytosis of apoptotic hepatocytes.15 A considerable amount of evidence thus suggests a critical role for the NOX2 isoform of NADPH oxidase in liver fibrogenesis. On the other hand, little is known about the role of NOX1 in the pathogenesis of liver fibrosis, although induction of NOX1 mRNA in the activated HSCs was reported.12 This led us to investigate whether the NOX1 isoform of NADPH oxidase is involved in the development of liver fibrosis using mice deficient in the Nox1 gene. We here report that NOX1 promotes the proliferation of HSCs and liver fibrogenesis by inactivating phosphatase and tensin homolog (PTEN). NOX1 thus positively regulates the Akt/FOXO4 pathway to reduce a cell cycle suppressor, p27kip1.