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ANXA3 Silencing Ameliorates Intracranial Aneurysm via Inhibition of the JNK Signaling Pathway.

ABSTRACT: Intracranial aneurysm (IA) rupture is a major cause of stroke death. Alteration of vascular smooth muscle cell (VSMC) function and phenotypic modulation plays a role in aneurysm progression. In the present study, we investigated the role of Annexin A3 (ANXA3) silencing in IA with the interaction of the c-Jun N-terminal kinase (JNK) signaling pathway. In IA and VSMCs of IA, the relationship between ANXA3 and the JNK signaling pathway was verified. To investigate the specific mechanism of ANXA3 silencing in IA, we transfected VSMCs with the overexpressed or small interfering RNA (siRNA) of ANXA3, or treated them with an inhibitor of the JNK signaling (SP600125). Cell counting kit-8 (CCK-8) assay was conducted to detect cell viability, and flow cytometry was conducted to assess cell cycle and apoptosis so as to evaluate the gain- and loss-of-function of ANXA3 and investigate the involvement of the JNK signaling pathway. The aneurysm wall of IA cells demonstrated an elevated level of ANXA3 expression and an activated JNK signaling pathway. VSMCs treated with siRNA-ANXA3 or SP600125 showed decreased expression of JNK, caspase-3, osteopontin (OPN), Bax, and matrix metalloproteinase-9 (MMP-9), as well as phosphate (p)-JNK, but increased the expression of α smooth muscle actin (α-SMA), β-tubulin, and Bcl-2. ANXA3 silencing or inactivation of the JNK signaling pathway also enhanced proliferation and repressed apoptosis of VSMCs. Collectively, this study shows that the silencing of ANXA3 can rescue VSMC function in IAs by inhibiting the phosphorylation and activation of the JNK signaling pathway. These findings may provide a potential therapy for the molecular treatment of IAs.

SUBMITTER: Wang Y

PROVIDER: S-EPMC6661453 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundNeuroinflammation is one of the most important pathogeneses in secondary brain injury after traumatic brain injury (TBI). Neutrophil extracellular traps (NETs) forming neutrophils were found throughout the brain tissue of TBI patients and elevated plasma NET biomarkers correlated with worse outcomes. However, the biological function and underlying mechanisms of NETs in TBI-induced neural damage are not yet fully understood. Here, we used Cl-amidine, a selective inhibitor of NETs to investigate the role of NETs in neural damage after TBI.MethodsControlled cortical impact model was performed to establish TBI. Cl-amidine, 2'3'-cGAMP (an activator of stimulating Interferon genes (STING)), C-176 (a selective STING inhibitor), and Kira6 [a selectively phosphorylated inositol-requiring enzyme-1 alpha [IRE1α] inhibitor] were administrated to explore the mechanism by which NETs promote neuroinflammation and neuronal apoptosis after TBI. Peptidyl arginine deiminase 4 (PAD4), an essential enzyme for neutrophil extracellular trap formation, is overexpressed with adenoviruses in the cortex of mice 1 day before TBI. The short-term neurobehavior tests, magnetic resonance imaging (MRI), laser speckle contrast imaging (LSCI), Evans blue extravasation assay, Fluoro-Jade C (FJC), TUNEL, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), western blotting, and quantitative-PCR were performed in this study.ResultsNeutrophils form NETs presenting in the circulation and brain at 3 days after TBI. NETs inhibitor Cl-amidine treatment improved short-term neurological functions, reduced cerebral lesion volume, reduced brain edema, and restored cerebral blood flow (CBF) after TBI. In addition, Cl-amidine exerted neuroprotective effects by attenuating BBB disruption, inhibiting immune cell infiltration, and alleviating neuronal death after TBI. Moreover, Cl-amidine treatment inhibited microglia/macrophage pro-inflammatory polarization and promoted anti-inflammatory polarization at 3 days after TBI. Mechanistically, STING ligand 2'3'-cGAMP abolished the neuroprotection of Cl-amidine via IRE1α/ASK1/JNK signaling pathway after TBI. Importantly, overexpression of PAD4 promotes neuroinflammation and neuronal death via the IRE1α/ASK1/JNK signaling pathway after TBI. However, STING inhibitor C-176 or IRE1α inhibitor Kira6 effectively abolished the neurodestructive effects of PAD4 overexpression after TBI.ConclusionAltogether, we are the first to demonstrate that NETs inhibition with Cl-amidine ameliorated neuroinflammation, neuronal apoptosis, and neurological deficits via STING-dependent IRE1α/ASK1/JNK signaling pathway after TBI. Thus, Cl-amidine treatment may provide a promising therapeutic approach for the early management of TBI.

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ANXA3 Silencing Ameliorates Intracranial Aneurysm via Inhibition of the JNK Signaling Pathway.

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