Therapeutic Targeting of Redox Signaling in Myofibroblast Differentiation and Age-Related Fibrotic Disease
Figure 3
Potential therapeutic targeting of myofibroblast differentiation in the treatment of age-associated fibrotic disease. Myofibroblast differentiation induced by TGFβ1 plays a central role in the etiology of numerous age-related fibrotic disorders. In particular, TGFβ induces a prooxidant shift in intracellular redox homeostasis via the induction of NOX4-derived ROS (in particular H2O2), which modulates downstream phosphorylation signaling cascades and transcriptional events that culminate in myofibroblast differentiation. The concomitant downregulation of selenium-dependent ROS scavenging enzymes by TGFβ further potentiates NOX4-derived ROS signaling, which also downregulates NO/cGMP signaling and thereby relieves inhibition of myofibroblast differentiation by NO. Fibroblast-to-myofibroblast differentiation and subsequent tissue fibrosis are reversible processes (broken horizontal arrow). Thus, pharmacological interference of these redox signaling processes to redress redox homeostasis and thereby restore the physiological fibroblast: myofibroblast ratio offers a promising therapeutic strategy for the treatment of age-related pathologies associated with myofibroblast dysregulation. Such pharmacological targeting may succeed at multiple levels. For example, targeting NOX4 directly via NOX4 inhibitors (NOX4i) or indirectly by ROS scavenging with Se or antioxidants would attenuate NOX4-derived ROS signaling and restore the inhibitory effects on differentiation by NO/cGMP signaling. Enhancing NO/cGMP signaling is also sufficient to prevent and reverse fibroblast-to-myofibroblast differentiation and may be achieved by (i) sGC stimulation using the NO donor sodium nitroprusside (SNP) and/or direct sGC stimulators/activators (BAY), (ii) promoting cGMP synthesis via administration of natriuretic peptides that bind to and activate transmembrane guanylyl cyclase natriuretic peptide receptors (NPRs), or (iii) by inhibiting phosphodiesterase (PDE)-mediated cGMP hydrolysis using PDE inhibitors (PDEi).
