In this study, we compared with the control group by using TMT-labeled proteomic method, which was found that there were 11 DEPs related to oxidative stress in human AAA tissues, the expression of NQO1was the most significantly up-regulated(3.1 fold). The expression of NQO1 was positively correlated with the swelling size of AAA and the level of ROS. In the senescence model of human VSMCs induced by AngII, it was found that inhibiting the expression of NQO1 promoted the accumulation of ROS and cell aging, suggesting that the increased expression of NQO1 could antagonize the cell injury induced by ROS accumulation.
NQO1 is a kind of luteinase located in the cytoplasm, which can catalyze the production of stable hydroquinone and protect cells against redox cycling of quinones and oxidative stress [8, 9]. However, NQO1 can also be directly reduced to unstable hydroquinone in some cases, leading to DNA alkylation or a large amount of ROS rapid production through via redox cycling [9, 10]. It has been reported that NQO1 can mitigate the oxidative DNA damage arising from the interplay intracellular ROS in post-mitotic ocular tissue . ROS is overproduced in the progression of AAA disease, which leads to the degradation of extracellular matrix and the change of VSMCs phenotype . It is found that the overexpression of NQO1 in AAA tissue antagonizes the oxidative stress damage caused by excessive ROS. Meanwhile, the high expression of NQO1 may be accompanied by the production of unstable hydroquinone, which promotes the production of a large number of ROS and aggravates the oxidative stress damage of blood vessels, suggesting that oxidative stress is expected to become a potential target for the treatment of AAA . It is of great significance to explore the role of NQO1 in AAA.
The overexpression of NQO1 in lung, gastric, colon, cervical, pancreatic and breast cancer is closely associated with poor patient prognosis . As a regulator of transcription factor NRF2, the increased expression of NQO1 in cancer cells contributes to tolerance to oxidative stress . The overexpression of NRF2/NQO1 in hepatocellular carcinoma was associated with tumor size, high α-fetoprotein, DES-γ-carboxy-prothrombin levels and multiple intrahepatic recurrences, could as an independent risk factor . It has been found that the potential mechanism of NQO1 promoting cancer cell proliferation is mainly through the activation of SIRT6/AKT/XIAP signal pathway  or by regulating the activity of STRI2 to regulate the process of mitosis . In this study, it was found that NQO1 expression was positively correlated with AAA size and ROS level. Silencing NQO1 expression promoted the oxidative stress damage and aging of VSMCs induced by AngII, which indicated that NQO1 played the role of antioxidant stress damage in AAA, but also showed that NQO1 expression could not balance the oxidative stress level of AAA, which led to the increase of NQO1 expression related to the histopathological severity of AAA, suggesting that it may become a biomarker of AAA. In addition, the up-regulated expression of NQO1 can slow down cell aging and play the anti-apoptosis role of VSMCs; furthermore, NQO1 promotes VSMCs proliferation by promoting mitosis and participates in intimal hyperplasia and pathological remodeling, the specific mechanism still needs to be further studied.
In this study, we found that among the 11 oxidative stress-related DEPs in AAA, the up-regulated proteins included NQO1, EPHX2 and ALDH18A1. Among them, the up-regulation of EPHX2 is related to endoplasmic reticulum stress in obesity, physical activity may reduce metabolic stress by inhibiting EPHX2 expression, and then activating PI3K/Akt/GSK3 β signal pathway to achieve the protective effect of antioxidant injury [17, 18]. Down-regulated proteins include Ndufs2, PNPO, CST3, AXL, NDUFA4L2, NDUFS6, MFGE8 and SUMO3, in which Ndufs2 is the core subunit of mitochondrial complex I, which can improve pulmonary vascular sensitivity during acute hypoxia and play an important protective role in hypoxic pulmonary vasoconstriction . It has been reported that CST3 has protective effects on various oxidative stress injuries that induce neuronal apoptosis . In the process of acute kidney injury (AKI) developing into chronic kidney disease (CKD), melatonin and Poricoic Acid A (PAA) in the early stage can up-regulate Gas6/AXL signal to attenuate the oxidative stress and inflammation in AKI, and in the later stage down-regulate Gas6/AXL signal to reduce renal fibrosis and CKD . It is inferred that AXL expression may be up-regulated in the stage of AAA formation and contribute to antioxidant stress. However, the expression may be down-regulated due to decompensation in ruptured AAA or giant aneurysms. It has been reported that the up-regulated expression of NDUFA4L2 improves the apoptosis of nucleus pulposus (NP) cells by inhibiting mitosis induced through oxidative stress . NDUFS6 is one of the important components of NADH, and NDUFS6 knockout mice can cause mitochondrial complex I deficiency specific cardiomyopathy, which reduces cardiomyocyte energy metabolism and mitochondrial function in mice, it is consistent with the clinical symptoms of patients with mitochondrial cardiomyopathy . MFGE8 can attenuate oxidative stress and brain injury after subarachnoid hemorrhage through integrin β-3-related molecular pathways [24, 25]. SUMO is a small ubiquitin-related modifier that could protect cells from various stressors including ischemia-reperfusion , while cellular oxidative stress leads to down-regulation of SUMO3 transcription . The results of this study are consistent with previous research reports, the expression of these proteins is decreased in AAA tissues, resulting in redox homeostasis imbalance. The up-regulated expression of NQO1 alone is not enough to maintain vascular homeostasis, so the oxidative stress in AAA is still at a high level.