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

Abstract

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 À/À ) 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.

<p>4-Octyl Itaconate Alleviates Lipopolysaccharide-Induced Acute Lung Injury in Mice by Inhibiting Oxidative Stress and Inflammation</p>

“…A previous study has demonstrated using Chromatin Immunoprecipitation (ChIP) that Nrf-2 is directly bound to the promoter regions of IL-1β and IL-6. 34 Nrf-2 reduced the production of mitochondrial ROS (mROS) to inhibit the hypoxia-inducible factor 1α (HIF-1α)/IL-1β signaling pathway by promoting the level of antioxidants. 35 In our study, OI reduced the expression of the inflammatory cytokines (IL-β, IL-6, and TNF-α) that could aggravate ALI by increasing lung inflammation.…”

The Emerging Application of Itaconate: Promising Molecular Targets and Therapeutic Opportunities

“…Furthermore, they also found that DI did not have the same effect on osteoclast function indicate that general electrophilic stress was probably not sufficient to induce the inhibition of osteoclastogenesis. In another research Zheng et al (2020) found 4-OI protected OB-6 cells and primary murine osteoblasts from oxidative injury, cell death, and apoptosis treated by H 2 O 2 through disassociation of Keap1 and Nrf2.…”

“…In two studies explored about the protective effect of DI to prevent the pathology inflammation of mastitis/endometritis diseases (Zhao et al, 2019;Xu et al, 2020). Injection of DI markedly decreased the production of pro-inflammatory cytokines, and increased the expression of Nrf2, HO-1 in LPSinduced mastitis and endometritis mice.…”

Itaconate ameliorates methicillin-resistant Staphylococcus aureus-induced acute lung injury through the Nrf2/ARE pathway

“…However, 4-OI can enter cells where it is hydrolyzed into itaconate. Recent studies have demonstrated that 4-OI can exert anti-inflammatory effects and reduce oxidative stress effects in various cell types (23)(24)(25). As an important cell affected by 4-OI, macrophages play an important role in the process of oxidative stress.…”