目的:脑动脉瘤(CA)被认为是最常见的脑血管疾病之一,影响着全世界数百万人。目前缺少用于治疗CA的治疗剂。Nesfatin-1(Nes-1)是82个氨基酸的脂肪因子,其具有广泛的生物学功能。然而,Nes-1在CA中的生理功能尚不清楚。这里,我们旨在评估Nes-1在CA病理发展中的预防作用,并阐明其背后的机制.
方法:我们使用了弹性蛋白酶诱导的CA模型,伴随着高盐饮食诱发高血压。此外,不同的实验技术,包括Verhoeff-VanGieson染色,实时PCR,酶联免疫吸附测定(ELISA),免疫荧光染色,被用来评估CA的形成,基因和蛋白质表达,以及巨噬细胞浸润。
结果:我们的结果表明Nes-1的给药显著减小了动脉瘤的大小。此外,Nes-1通过抑制白细胞介素-6(IL-6)的表达来预防炎症反应,肿瘤坏死因子-α(TNF-α),和单核细胞趋化蛋白1(MCP-1)在威利斯环(COW)区域的mRNA和蛋白质水平。此外,Nes-1降低了COW区基质金属蛋白酶-2(MMP-2)和基质金属蛋白酶-9(MMP-9)的水平。我们发现Nes-1的给药抑制了巨噬细胞的侵袭。机械上,Nes-1通过促进Nrf-2的核转位激活,但阻止了IκBα/NF-κB信号通路的激活。
结论:这些研究结果表明,Nes-1可能是预防CA的一种有前景的药物。
OBJECTIVE: Cerebral aneurysm (CA) has been considered one of the most common cerebrovascular diseases, affecting millions of people worldwide. A therapeutic agent is currently missing for the treatment of CA. Nesfatin-1 (Nes-1) is an 82-amino acid adipokine which possesses a wide range of biological functions. However, the physiological function of Nes-1 in CA is still unknown. Here, we aimed to assess the preventive effects of Nes-1 in the pathological development of CA and elucidate the mechanisms behind this.
METHODS: We used an elastase-induced CA model, accompanied by a high-salt diet to induce hypertension. Additionally, diverse experimental techniques, including Verhoeff-Van Gieson staining, real time PCR, enzyme-linked immuno sorbent assay (ELISA), and immunofluorescence staining, were employed to assess CA formation, gene and protein expression, as well as the macrophage infiltration.
RESULTS: Our results indicate that administration of Nes-1 significantly decreased the aneurysm size. Additionally, Nes-1 prevented inflammatory response by inhibiting the expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein 1 (MCP-1) at both the mRNA and protein levels in the Circle of Willis (COW) region. Also, the increased levels of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in the COW region were reduced by Nes-1. We found that Nes-1 administration suppressed the invasion of macrophages. Mechanistically, Nes-1 activated Nrf-2 by promoting its nuclear translocation but prevented the activation of the IκBα/NF-κB signaling pathway.
CONCLUSIONS: These findings suggest that Nes-1 might be used as a promising agent for the prevention of CA.