Itaconate prevents abdominal aortic aneurysm formation through inhibiting inflammation via activation of Nrf2

EBioMedicine

Tong Xu¹  Xiaofei Feng²  Hao Zheng²  Guoquan Wei²  Jianping Bin²  Yang Yang²  Haoyu Song²  Xiang He²  Wangjun Liao²  Yanxian Lai²  Lintao Zhong²  Yulin Liao³ 

[1] Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China;Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, China;Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China;

关键词: Itaconate;    Abdominal aortic aneurysm;    Angiotensin II;    Inflammation;   

DOI  :  

来源: DOAJ

【 摘 要 】

Absract:Background: Identifying effective drugs to suppress vascular inflammation is a promising strategy to delay the progression of abdominal aortic aneurysm (AAA). Itaconate has a vital role in regulating inflammatory activation in various inflammatory diseases. However, the role of itaconate in the progression of AAA is unknown. In this study, we explored the inhibitory effect of itaconate on AAA formation and its underlying mechanisms. Methods: Quantitative PCR, western blotting and immunohistochemistry were used to determine Irg1 and downstream Nrf2 expression in human and mouse AAA samples. Liquid chromatograph-mass spectrometry (LC-MS) analysis was performed to measure the abundance of itaconate. OI treatment and Irg1 knockdown were performed to study the role of OI in AAA formation. Nrf2 intervention in vivo was performed to detect the critical role of Nrf2 in the beneficial effect of OI on AAA. Findings: We found that itaconate suppressed the formation of angiotensin II (Ang II)-induced AAA in apolipoprotein E-deficient (Apoe−/−) mice, while Irg1 deficiency exerted the opposite effect. Mechanistically, itaconate inhibited vascular inflammation by enabling Nrf2 to function as a transcriptional repressor of downstream inflammatory genes via alkylation of Keap1. Moreover, Nrf2 deficiency significantly aggravated inflammatory factor expression and promoted AAA formation. In addition, Keap1 overexpression significantly promoted Ang II-induced AAA formation, which was inhibited by itaconate. Interpretation: Itaconate inhibited AAA formation by suppressing vascular inflammation, and therapeutic approaches to increase itaconate are potentially beneficial for preventing AAA formation. Funding: National Natural Science Foundations of China and Guangzhou regenerative medicine and Health Laboratory of Guangdong.

【 授权许可】

Unknown