Oxydative stress and vascular aging (WP1) : A Taieb, H Reza Rezvani, C Helmer, I Forfar, MA Renault, F Xuereb, MN Delyfer, P Dufourcq (Inserm U1035; Inserm U897; Inserm U1034; - Department of Ophthalmology. Medical Unit « Rétine, Uvéites et Neuro-Ophtalmologie »)
The dual role of ROS
Reactive oxygen species (ROS) has a dual role in physiology which is dependent on the amount, duration, and localization of their production. While prolonged exposure to high ROS concentrations may lead to non-specific damage to proteins, lipids, and nucleic acids (indispensable in host defense), low to intermediate ROS concentrations exert their effects through regulation of cell signaling pathways (critical for normal physiological processes through redox regulation of protein phosphorylation, ion channels, and transcription factors). Indeed at low, regulated levels, ROS participate in the regulation of many cellular processes, including differentiation, proliferation, growth, apoptosis, cytoskeletal regulation, migration, and contraction.
Considering this dual role of ROS, ROS-related disease can thus be due to a lack of ROS (e.g., chronic granulomatous disease, certain autoimmune disorders) or a surplus of ROS (e.g., age-associated disease such as cardiovascular and neurodegenerative diseases). For diseases caused by a surplus of ROS, antioxidant supplementation has proven largely ineffective in clinical studies, most probably because the action of antioxidants comes too late, at too low dosages, and is in part non-specific. Specific inhibition of ROS-producing enzymes is an approach more promising to reach clinical efficacy.
A new specific NOX-1 peptide inhibitor
The key producers of ROS in many cells are the family of NADPH oxidase (NOX) complexes, of which there are seven members (NOX1 to NOX5, DUOX1 and DUOX2), with various tissue distribution and activation mechanisms. We have recently shown that NOX-1 overactivation plays a causal role in premature skin aging and that inhibition of NOX-1 activation blocks premature skin aging features (Hosseini et al., 2015). To achieve these results, we have developed a new specific NOX-1 peptide inhibitor, hereafter called InhNOX, which blocks NOX-1 activity in human and mice. The InhNOX peptide is a heptameric oligomer that blocks the interaction between NOX activator 1 (NOXA1) and NOX organizer 1 (NOXO1), two subunits of NOX-1 complex which should assemble with NOX1, p22 and Rac to form a full activated NOX-1 complex. This inhibitor has been patented and an orphan drug designation for treatment of xeroderma pigmentosum has been obtained in November 2014 at the European Medicines Agency.
Effects of InhNOX on endothelial cells
Although various vascular wall cells express multiple NOX (endothelial cells express NOX1, NOX2, NOX4 and NOX5; vascular smooth muscle cells express NOX1, NOX4 and NOX5; and adventitial fibroblasts express NOX2 and NOX4), NOX1 and NOX2 oxidases have been documented to be the major sources of ROS in the vascular wall in conditions such as hypertension, hypercholesterolaemia, fibrosis, diabetes and ageing (Donato et al., 2015; Drummond et al., 2015; Krauze et al., 2007). Therefore, we are interested in the exploration of the effects of InhNOX on endothelial cells as well as on different vascular diseases such as diabetic neuropathy and retinopathy.
- WP1.2 - Diet, antioxidants and vascular aging: epidemiological aspects
- WP 2.2 - Preclinical proof of concept of an anti-NOX1 peptide in vascular aging
- Effect of the anti-NOX1 peptide on endothelial cell metabolism
- Effect of the anti-NOX-1 peptide in protecting vessel / nerve alteration in diabetes
- Pharmacokinetic / Pharmacodynamic study of the anti-NOX-1 peptide
- Role in retinal protection in diabetic retinopathy