| BackgroundAbdominal aortic aneurysm(AAA)is a chronic inflammatory disease.Regulating the expression of inflammation-related genes is a promising strategy to control the progression of abdominal aortic aneurysm.In many studies,knockout/in of genes or transfection of viruses(such as lentivirus,adeno-associated virus or adenovirus)have been used to regulate the expression of inflammation-related genes thus to attenuate AAA formation.In addition,studies have suggested that injection of monoclonal antibodies against inflammatory factor receptors inhibits the formation and progression of aneurysms.However,these gene editing tools and monoclonal antibodies are expensive,and long-term injection of virus or monoclonal antibodies lead to drug resistance and efficacy reduction.In addition,ethical issues involved in gene editing tools used in clinical treatment.Recently,studies have shown that endogenous metabolites play a key role in the progression of various pathological processes.This kind of natural chemical compound is relatively inexpensive and easy to synthesize in large quantities,which promoted the implementation of clinical trials of some metabolite-derived drugs in many diseases.Metabolites have the potential to be a novel and inexpensive treatment options for AAA.To develop this potential,we need to identify metabolites that can be used to treat aortic aneurysms and demonstrate their role in AAA models.A recent study showed that upon inflammatory mediator stimuli,macrophages metabolite itaconate was significantly upregulated,which had a feedback inhibiton of inflammation reaction of macrophages.Knock down of Irgl,the encode gene of key enzyme of itaconate production,promoted inflammatory factors secretion.In vivo experiments have shown anti-inflammatory effects when mice were administered itaconate during psoriasis,sepsis and ischemia-reperfusion injury.Itaconate plays an important role in the regulation of inflammatory response during the process of inflammatory disease.However,the role of itaconate in the AAA formation and development is unclear.Based on our previous findings that itaconate was significantly upregulated in mouse AAA tissues,we speculate that itaconate may also play an anti-inflammatory role in AAA process.In this study,we explored the effect of itaconate on AAA formation and its underlying mechanism.Methods1.Diffrential analysis of itaconate/irgl in AAAs and normal aortas:Real-time quantitative polymerase chain reaction(rt-qPCR),western blot and immunohistochemistry were used to determine Irgl and Nrf2 expression in human and mouse AAA samples.Liquid chromatograph-mass spectrometry(LC-MS)analysis was performed to measure the abundance of itaconate.2.Explore the effects of itaconate addition and inhibition of itaconate production by Irgl knockdown on AAA formation in mice:Intraabdominal injection of itaconate and knockdown of Irg1 to analyze the AAA incidence,mortality,maximal aortic diameter,elastin degradation,macrophage infiltration and the expression of inflammatory factors.3.Explore the mechanism of itaconate on AAA:Addition of itaconate and Knockdown of irg1 in mouse peritoneal macrophages and mouse RAW264.7 cells to detect the expression of inflammatory factors and matrix metalloproteinases,as well as the expression of downstream Nrf2,and then explore the role of Nrf2 in AAA.ResultsWe found that itaconate suppressed the formation of mouse AAA,while Irgl deficiency exerted the opposite effects.Mechanistically,itaconate inhibited vascular inflammation by enabling Nrf2 to function as a transcriptional repressor of downstream inflammatory genes via alkylation of Keap1.Moreover,Nrf2 overexpression inhibited AAA formation by attenuating inflammatory reaction,while Nrf2 knockdown promoted AAA formation by aggravating inflammatory reaction.ConclusionItaconate inhibited AAA formation by suppressing vascular inflammation,and therapeutic approaches to increase itaconate are potentially beneficial for preventing AAA formation. |
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