Role of NADPH oxidases in the redox biology: Towards an intelligent inhibition of Oxidative Stress

CASTRO C

Workshop; Frontiers in Biosciences; 2023

SIIP-Universidad Nacionalde Cuyo

NADPH oxidases (NOX) are a family of transmembrane enzymes with the sole purpose of generating reactive oxygen species (ROS). Oxidative stress and redox dysregulation are typical features of numerous diseases and uncontrolled NOX activity represents a major source of free radicals in pathological oxidative damage. NOX inhibitors have high potential as a therapy for a wide range of diseases, including cardiovascular pathologies and diabetes. In humans, four NOX isoforms are present in the vascular wall (NOX1, NOX2, NOX4, and NOX5). The specific roles of NOX1, NOX2, and 4 as contributors to cardiovascular pathologies have been the focus of extensive research, but evidence about NOX5 in animal models is scarce because the Nox5 gene is absent in rodents. Nevertheless, recent evidence points towards the role of increased NOX5 activity as a key contributor to atherosclerosis, hypertension, diabetic nephropathy, and stroke. Based on the rationale that NOX5 inhibitors have therapeutic value for human health, we performed a high throughput screening and identified several potent inhibitors of NOX5. In the present project, two axes of research were followed: (i) at the University of Geneva, Switzerland (UNIGE), we focused on in vitro optimization of NOX5 inhibitors and identified several molecules with low micromolar inhibitory activity on NOX5; (ii) at the Universidad Nacional de Cuyo, Argentina focused on the measurement of NOX5 activity and NOX5 expression in human tissue. For this, vascular cells from rabbits and humans were cultured in pro-inflammatory and proliferative conditions, showing increased ROS generation, and providing an optimal vascular system to test NOX5 inhibitors. Altogether, this Seed money grant has set the bases for further characterization of this original and poorly understood therapeutic approach for vascular diseases in humans.