PMID- 36336010 OWN - NLM STAT- MEDLINE DCOM- 20221122 LR - 20221122 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 936 DP - 2022 Dec 5 TI - 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. PG - 175361 LID - S0014-2999(22)00622-7 [pii] LID - 10.1016/j.ejphar.2022.175361 [doi] AB - BACKGROUND: Thoracic aortic aneurysm and dissection (TAAD) is caused by the apoptosis and phenotypic transformation of vascular smooth muscle cells (VSMCs). The dysfunction of VSMCs affects their secretion of chemokines 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 promoted 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. CI - Copyright (c) 2022 Elsevier B.V. All rights reserved. FAU - Wang, Dashuai AU - Wang D AD - Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, China; Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, JieFang Road 1277, Wuhan, 430022, China. FAU - Wu, Jia AU - Wu J AD - Key Laboratory for Molecular Diagnosis of Hubei Province, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, ShengLi Street 26, Wuhan, 430014, China. FAU - Le, Sheng AU - Le S AD - Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, JieFang Road 1277, Wuhan, 430022, China; Department of Thoracic Surgery (S.L.), Zhongnan Hospital of Wuhan University, Wuhan University, East Lake Road 169, Wuhan, 430072, China. FAU - Wang, Hongfei AU - Wang H AD - Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, JieFang Road 1277, Wuhan, 430022, China. FAU - Luo, Jingjing AU - Luo J AD - Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, JieFang Road 1277, Wuhan, 430022, China. FAU - Li, Rui AU - Li R AD - Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, JieFang Road 1277, Wuhan, 430022, China. FAU - Chen, Xing AU - Chen X AD - Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, JieFang Road 1277, Wuhan, 430022, China. FAU - Song, Yu AU - Song Y AD - Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, JieFang Road 1277, Wuhan, 430022, China. FAU - Wu, Long AU - Wu L AD - Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, JieFang Road 1277, Wuhan, 430022, China. FAU - Ye, Ping AU - Ye P AD - Key Laboratory for Molecular Diagnosis of Hubei Province, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, ShengLi Street 26, Wuhan, 430014, China; Department of Cardiology, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, ShengLi Street 26, Wuhan, 430014, China. Electronic address: blue314@163.com. FAU - Du, Xinling AU - Du X AD - Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, JieFang Road 1277, Wuhan, 430022, China. Electronic address: xinlingdu@hust.edu.cn. FAU - Huang, Xiaofan AU - Huang X AD - Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, JieFang Road 1277, Wuhan, 430022, China. Electronic address: dr_xfhuang@hust.edu.cn. LA - eng PT - Journal Article DEP - 20221103 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 6N510JUL1Y (oltipraz) RN - 0 (Inflammasomes) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Reactive Oxygen Species) RN - 0 (NF-E2-Related Factor 2) RN - 151-18-8 (Aminopropionitrile) RN - 80321-89-7 (1,3,4,6-tetra-O-acetyl-2-azido-2-deoxyglucopyranose) RN - 0 (Nlrp3 protein, mouse) SB - IM MH - Mice MH - Animals MH - *Aorta, Thoracic MH - Inflammasomes MH - NLR Family, Pyrin Domain-Containing 3 Protein MH - Reactive Oxygen Species MH - NF-E2-Related Factor 2 MH - Aminopropionitrile MH - *Aneurysm OTO - NOTNLM OT - Monocyte chemoattractant protein-1 OT - NLRP3 inflammasome OT - Nuclear factor erythroid 2-related factor 2 OT - Oltipraz OT - Thoracic aortic aneurysm and dissection OT - Vascular smooth muscle cells COIS- Declaration of competing interest The authors declare no conflicts of interest. EDAT- 2022/11/07 06:00 MHDA- 2022/11/23 06:00 CRDT- 2022/11/06 19:33 PHST- 2022/04/28 00:00 [received] PHST- 2022/10/16 00:00 [revised] PHST- 2022/10/31 00:00 [accepted] PHST- 2022/11/07 06:00 [pubmed] PHST- 2022/11/23 06:00 [medline] PHST- 2022/11/06 19:33 [entrez] AID - S0014-2999(22)00622-7 [pii] AID - 10.1016/j.ejphar.2022.175361 [doi] PST - ppublish SO - Eur J Pharmacol. 2022 Dec 5;936:175361. doi: 10.1016/j.ejphar.2022.175361. Epub 2022 Nov 3.