Redox Signaling as a Therapeutic Target to Inhibit Myofibroblast Activation in Degenerative Fibrotic Disease

Figure 3

Potential therapeutic targeting of myofibroblast differentiation. Myofibroblast differentiation plays a central role in the etiology of fibrosis. TGFβ, which is widely considered the foremost inducer of fibrosis, induces NOX4 resulting in a persistent prooxidant shift in intracellular redox homeostasis mediated via ROS (in particular H₂O₂), which modulates downstream phosphorylation signaling cascades and transcriptional events culminating in fibroblast-to-myofibroblast differentiation. The concomitant downregulation of selenium (Se)-dependent ROS scavenging enzymes by TGFβ further potentiates NOX4-derived ROS signaling. In parallel, TGFβ and H₂O₂ attenuate NO signaling, which is associated with the fibroblast phenotype, via attenuation of NOS and sGC activities. Likewise, NOS inhibitors (NOSi/L-NAME) attenuate NO signaling and aggravate fibrosis. Fibroblast-to-myofibroblast differentiation and subsequent tissue fibrosis are reversible processes. Thus, targeting persistent NOX4-derived ROS levels in the diseased tissue by NOX4 inhibitors (NOX4i) or by ROS scavenging with Se or antioxidants results in inhibition of myofibroblast differentiation and, moreover, in dedifferentiation/inactivation of myofibroblasts to a quiescent fibroblast-like phenotype. Similarly, enhancement of NO signaling by administration of the NOS substrate L-arginine, NO-donors (SNP/SNAC), sGC stimulators/activators, or PDE inhibitors (PDEi) maintains the fibroblast phenotype or induces dedifferentiation/inactivation of preexisting myofibroblasts.