Oltipraz, the activator of nuclear factor erythroid 2-related factor 2 (Nrf2), protects against the formation of BAPN-induced aneurysms and dissection of the thoracic aorta in mice by inhibiting activation of the ROS-mediated NLRP3 inflammasome

Background: Thoracic aortic aneurysm and dissection (TAAD) is caused by the apoptosis and phenotypic trans-formation of vascular smooth muscle cells (VSMCs). The dysfunction of VSMCs affects their secretion of che-mokines such as monocyte chemoattractant protein-1 (MCP-1) to recruit the infiltration of macrophages which release proinflammatory cytokines and matrix metalloproteinases (MMPs) to accelerate the process of TAAD formation. Approach and results: We analyzed the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) in aortic tissues of TAAD patients and the beta-aminopropionitrile fumarate (BAPN)-induced mouse model, and the levels of Nrf2 were elevated in both aortic lesions. Treatment with the Nrf2 activator oltipraz protects against the formation of BAPN-induced aneurysm and dissection, as demonstrated by a higher survival rate, postponing the time of aortic rupture, and inhibiting aortic luminal dilation. In addition, the thoracic aortas of BAPN-treated mice inhibited the apoptosis and phenotypic transformation of VSMCs. When treated with oltipraz, they had reduced macrophage infiltration proinflammatory cytokines and MMPs. Furthermore, oltipraz treatment pro-moted the translocation of Nrf2 and downregulated the NLRP3 pathway. Conclusion: Nrf2 plays a crucial role in protecting against TAAD development, and persistent activation of Nrf2 is a promising therapeutic strategy against the progression of TAAD.