Nrf2 deficiency aggravates PM(2.5)-induced cardiomyopathy by enhancing oxidative stress, fibrosis and inflammation via RIPK3-regulated mitochondrial disorder

PM(2.5) is a well-known air pollutant threatening public health, and long-term exposure to PM(2.5) increases the risk of cardiovascular diseases. Nrf2 plays a pivotal role in the amelioration of PM(2.5)-induced lung injury. However, if Nrf2 is involved in PM(2.5)-induced heart injury, and the underlying molecular mechanisms have not been explored. In this study, wild type (Nrf2(+/+)) and Nrf2 knockout (Nrf2(-/-)) mice were exposed to PM(2.5) for 6 months. After PM(2.5) exposure, Nrf2(-/-) mice developed severe physiological changes, lung injury and cardiac dysfunction. In the PM(2.5)-exposed hearts, Nrf2 deficiency caused significant collagen accumulation through promoting the expression of fibrosis-associated signals. Additionally, Nrf2(-/-) mice exhibited greater oxidative stress in cardiac tissues after PM(2.5) exposure. Furthermore, PM(2.5)-induced inflammation in heart samples were accelerated in Nrf2(-/-) mice through promoting inhibitor of α/nuclear factor κB (IκBα/NF-κB) signaling pathways. We also found that Nrf2(-/-) aggravated autophagy initiation and glucose metabolism disorder in hearts of mice with PM(2.5) challenge. Cardiac receptor-interacting protein kinase 3 (RIPK3) expression triggered by PM(2.5) was further enhanced in mice with the loss of Nrf2. Collectively, these results suggested that strategies for enhancing Nrf2 could be used to treat PM(2.5)-induced cardiovascular diseases.