Redox Signaling as a Therapeutic Target to Inhibit Myofibroblast Activation in Degenerative Fibrotic Disease
Figure 2
Signaling pathways that activate NOX4 and downstream targets of NOX4-derived ROS in myofibroblasts. NOX4 activity is predominantly regulated at the transcriptional level [59, 65]. TGFβ is one of the main inducers of NOX4 during myofibroblast activation. Additionally, hypoxia, angiotensin II, and platelet-derived growth factor (PDGF) have also been shown to activate NOX4 expression leading to myofibroblast activation; however, this most likely occurs as a result of their indirect activation of TGFβ signaling [75–77]. Upon binding of TGFβ ligand, heteromeric complexes of TGFβ receptor type I and type II recruit and activate the canonical signal transducers Smad2/3 as well as less well understood noncanonical signal transducers, such as mitogen-activated protein kinases (MAPKs) and protein kinase C (PKC). TGFβ signal transducers subsequently activate the transcription of target genes that include NOX4. TGFβ-mediated induction of NOX4 expression has largely shown to be Smad2/3-dependent [39, 40]; however, PKC has also been implicated in TGFβ-dependent upregulation of NOX4 [78]. The subcellular localization of NOX4 appears to be cell-, tissue-, and perhaps even context-specific with its reported localization to the plasma membrane (PM), endoplasmic reticulum (ER), nucleus, focal adhesions, and mitochondria [62]. NOX4 requires the cofactor for production of ROS, of which predominantly H2O2 is detected [59–61]. NOX4-derived H2O2 activates signaling intermediates such as Smad2/3, ERK1/2, JNK and Src [26, 39, 40, 77, 79–81], which subsequently induce the transcription of downstream target genes, such as α-smooth muscle cell actin (α-SMA), collagens, and fibronectin leading to ECM deposition and myofibroblast differentiation/activation.
