AEBP1 Promotes the Occurrence and Development of Abdominal Aortic Aneurysm by Modulating Inflammation via the NF-κB Pathway

Abstract

Inflammation plays a significant role in the pathogenesis of human abdominal aortic aneurysm (AAA). AEBP1 can promote activation of the NF-B pathway, subsequently affecting the expression of NF-B target genes, including inflammatory cytokines and matrix metalloproteinases (MMPs). Our objective was to examine the role of AEBP1 in the development of AAA and characterize the underlying mechanism.Methods: ITRAQ, RT-PCR, western blot, immunohistochemistry, and ELISA were used to compare different experimental groups with the controls and to determine the differentially expressed genes. We generated an AAA model using porcine pancreatic elastase in Sprague-Dawley rats and silenced their AEBP1 in vivo by adenoviruses injected intra-adventitially. We also silenced or overexpressed AEBP1 in human vascular smooth muscle cells in vitro in the presence and in the absence of NF-B inhibitor BAY 11-7082.Results: Proteome iTRAQ revealed a high expression of AEBP1 in AAA patients, which was verified by qRT-PCR, western blot, immunohistochemistry, and ELISA. The mean expression level of AEBP1 in AAA patients was higher than that in controls. Along with AEBP1 upregulation, we also verified mis-activation of NF-B in human AAA samples. The in vivo studies indicated that AEBP1 knockdown suppressed AAA progression. Finally, the in vitro studies illustrated that AEBP1 promotes activation of the NF-B pathway, subsequently upregulating pro-inflammatory factors and MMPs. Conclusions:Our results indicate a role of AEBP1 in the pathogenesis of AAA and provide a novel insight into how AEBP1 causes the development of AAA by activating the NF-B pathway.typical pathological signatures of AAA include inflammatory infiltration in the adventitia and tunica media, aortic elastin proteolytic degradation, and pathological remodeling 4) . Vascular inflammation has been regarded as the primary determinant of AAA 5) . It proceeds with gradual infiltration of many inflammatory cell types, including macrophages, lymphocytes, mast cells, and neutrophils, into the intima from the adven-Copyright©2019 Japan Atherosclerosis Society This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.

Human Umbilical Cord Mesenchymal Stem Cells Attenuate Abdominal Aortic Aneurysm Progression in Sprague-Dawley Rats: Implication of Vascular Smooth Muscle Cell Phenotypic Modulation

“…Intraluminal perfusion with elastase model, one of the most widely used experimental models of AAA in vivo, was first introduced by Anidjar et al in Wistar rats [ 27 ], which simulates the pathological characteristics of medial degeneration and leukocyte infiltration in the occurrence and development of human AAA [ 28 , 29 ]. In this study, we established the elastase-induced AAA model in SD rats, and the abdominal aortas were morphologically aneurysmal on the 14th postoperative day, which is consist with previous investigations [ 24 , 30 ].…”

“…In this study, elastase infusion method was implemented to establish an in vivo model of AAA in male SD rats following previous established protocols [24]. Briefly, after animals were anesthetized with gas mixture of 2% isoflurane and 2 L/min oxygen, midline abdominal incision was performed, the segment between left renal vein and bifurcation of abdominal aorta was carefully isolated and exposed, and then the infrarenal abdominal aorta was perfused with elastase (30 U/mL; Solarbio Life Sciences) or saline through PE-10 catheter under 130 cm water column pressure for 30 min.…”

AEBP1 is a Novel Oncogene: Mechanisms of Action and Signaling Pathways

“…Interestingly, the nuclear localization of NF-κB/p65 was observed in specific neurons with AEBP1 overexpression [24]. AEBP1 has also been shown to play a role in abdominal aortic aneurysm (AAA) [25]. AEBP1 overexpression in AAA results in the activation of NF-κB/p65 and the consequent upregulation of inflammatory cytokines IL-1β, IL-6, TNFα, and MCP-1, as well as MMP2 and MMP-9, matrix metalloproteinases (MMPs) [25].…”

“…AEBP1 has also been shown to play a role in abdominal aortic aneurysm (AAA) [25]. AEBP1 overexpression in AAA results in the activation of NF-κB/p65 and the consequent upregulation of inflammatory cytokines IL-1β, IL-6, TNFα, and MCP-1, as well as MMP2 and MMP-9, matrix metalloproteinases (MMPs) [25]. In addition, modulation of AEBP1 expression has been implicated in other processes and conditions such as adipogenesis [2,5,6,11,26,27], mammary gland development [28][29][30], macrophage cholesterol homeostasis [8,12,31], inflammation [8,25,28,32], and atherosclerosis [32].…”

AEBP1 Promotes Glioblastoma Progression and Activates the Classical NF-κB Pathway

“…The AEBP1 protein could positively regulate the activity of MAP kinase (MAPK) in adipocytes, thus stimulating adipocyte proliferation and reducing adipocyte differentiation; the proteins can also positively regulate NF- κ B activity in macrophages by promoting I-kappa-B-alpha (NFKBIA) phosphorylation and subsequent degradation, thereby enhancing the inflammatory responsiveness of macrophages [ 5 ]. AEBP1 is involved in the progression of a variety of diseases, such as abdominal aortic aneurysm [ 6 ], nonalcoholic steatohepatitis [ 7 ], Ehlers-Danlos syndrome [ 8 ], and Alzheimer's disease [ 9 ]. Studies have shown that AEBP1 is highly expressed in a variety of malignant tumors (such as breast cancer, glioblastoma, bladder cancer, gastric cancer, colorectal cancer, ovarian cancer, and skin cancer) [ 5 ].…”