Reciprocal regulation of NRF2 by autophagy and ubiquitin–proteasome modulates vascular endothelial injury induced by copper oxide nanoparticles.

NRF2 is the key antioxidant molecule to maintain redox homeostasis, however the intrinsic mechanisms of NRF2 activation in the context of nanoparticles (NPs) exposure remain unclear. In this study, we revealed that copper oxide NPs (CuONPs) exposure activated NRF2 pathway in vascular endothelial cells. NRF2 knockout remarkably aggravated oxidative stress, which were remarkably mitigated by ROS scavenger. We also demonstrated that KEAP1 (the negative regulator of NRF2) was not primarily involved in NRF2 activation in that KEAP1 knockdown did not significantly affect CuONPs-induced NRF2 activation. Notably, we demonstrated that autophagy promoted NRF2 activation as evidenced by that ATG5 knockout or autophagy inhibitors significantly blocked NRF2 pathway. Mechanically, CuONPs disturbed ubiquitin–proteasome pathway and consequently inhibited the proteasome-dependent degradation of NRF2. However, autophagy deficiency reciprocally promoted proteasome activity, leading to the acceleration of degradation of NRF2 via ubiquitin–proteasome pathway. In addition, the notion that the reciprocal regulation of NRF2 by autophagy and ubiquitin–proteasome was further proven in a CuONPs pulmonary exposure mice model. Together, this study uncovers a novel regulatory mechanism of NRF2 activation by protein degradation machineries in response to CuONPs exposure, which opens a novel intriguing scenario to uncover therapeutic strategies against NPs-induced vascular injury and disease. Highlights: CuONPs exposure activates NRF2 signaling in vascular endothelial cells and mouse thoracic aorta. KEAP1 is dispensable for NRF2 activation in CuONPs-treated vascular endothelial cells. CuONPs-induced autophagy facilitates NRF2 activation in vascular endothelial cells and mouse thoracic aorta. Autophagy and ubiquitin–proteasome reciprocally regulate NRF2 activation in CuONPs-treated vascular endothelial cells and mouse thoracic aorta. [ABSTRACT FROM AUTHOR]