Apc gene suppresses intracranial aneurysm formation and rupture through inhibiting the NF-κB signaling pathway mediated inflammatory response - PubMed (original) (raw)

. 2019 Mar 26;39(3):BSR20181909.

doi: 10.1042/BSR20181909. Print 2019 Mar 29.

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Apc gene suppresses intracranial aneurysm formation and rupture through inhibiting the NF-κB signaling pathway mediated inflammatory response

Xian-Liang Lai et al. Biosci Rep. 2019.

Expression of concern in

Abstract

Background: Intracranial aneurysm (IA) is a critical acquired cerebrovascular disease that may cause subarachnoid hemorrhage, and nuclear factor-κB (NF-κB)-mediated inflammation is involved in the pathogenesis of IA. Adenomatous polyposis coli (Apc) gene is a tumor suppressor gene associated with both familial and sporadic cancer. Herein, the purpose of our study is to validate effect of Apc gene on IA formation and rupture by regulating the NF-κB signaling pathway mediated inflammatory response. Methods: We collected IA specimens (from incarceration of IA) and normal cerebral arteries (from surgery of traumatic brain injury) to examine expression of Apc and the NF-κB signaling pathway related factors (NF-κB p65 and IκBα). ELISA was used to determine levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β (IL-1β), and IL-6. IA model was established in rats, and Apc-siRNA was treated to verify effect of Apc on IA formation and rupture. Next, regulation of Apc on the NF-κB signaling pathway was investigated. Results: Reduced expression of Apc and IκBα, and increased expression of NF-κB p65 were found in IA tissues. MCP-1, TNF-α, IL-1β, and IL-6 exhibited higher levels in unruptured and ruptured IA, which suggested facilitated inflammatory responses. In addition, the IA rats injected with Apc-siRNA showed further enhanced activation of NF-κB signaling pathway, and up-regulated levels of MCP-1, TNF-α, IL-1β, IL-6, MMP-2, and MMP-9 as well as extent of p65 phosphorylation in IA. Conclusion: Above all, Apc has the potential role to attenuate IA formation and rupture by inhibiting inflammatory response through repressing the activation of the NF-κB signaling pathway.

Keywords: Apc gene; Inflammatory response; Intracranial aneurysm; NF-κB signaling pathway.

© 2019 The Author(s).

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Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1

Figure 1. Down-regulation of Apc and IκBα and up-regulation of NF-κB p65 in unruptured and ruptured IA tissues were revealed by immunohistochemstry (× 400)

(A) Immunohistochemical staining for protein Apc, NF-κB p65, and IκBα in normal vascular tissues, unruptured and ruptured IA tissues. (B) Quantitative analysis for positive expression rate; *P<0.05 compared with normal vascular tissues.

Figure 2

Figure 2. siRNA-1 and siRNA-3 exhibit the highest interference efficiency and are selected for the following experiments

(A) The mRNA expression of Apc in the siRNA-1, siRNA-2, and siRNA-3 groups detected by RT-qPCR. (B,C) Protein expression of Apc in the siRNA-1, siRNA-2, and siRNA-3 groups detected by Western blot analysis; *P<0.05 compared with the NC group.

Figure 3

Figure 3. HE staining (×400) demonstrates that silencing of Apc promotes the histopathological changes of IA with slowly disappeared IA endodermis, greatly degenerated VSMC, dramatically declined number and layers of VSMCs, severely fractured elastic fiber, and increased inflammatory cell infiltration

Figure 4

Figure 4. Silencing of Apc contributed to up-regulation of the mRNA expression of NF-κB p65, MMP-2, MMP-9, TNF-α, and IL-1β, and down-regulation of Apc and IκBα according to detection of RT-qPCR

*P<0.05 compared with the normal group; #P<0.05 compared with the blank and NC groups.

Figure 5

Figure 5. Silencing of Apc contributed to up-regulation of the protein expression of NF-κB p65, MMP-2, MMP-9, TNF-α, and IL-1β, and down-regulation of Apc and IκBα according to detection by Western blot analysis

(A) Protein bands of NF-κB p65, MMP-2, MMP-9, TNF-α, IL-1β, IL-6, Apc, and IκBα as well as extent of p65 phosphorylation in rats in each group. (B) Quantitative analysis of protein expression of NF-κB p65, MMP-2, MMP-9, TNF-α, IL-1β, IL-6, Apc, and IκBα, as well as the extent of p65 phosphorylation of rats in each group; *P<0.05 compared with the normal group; #P<0.05 compared with the blank and NC groups.

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