Liu Hongyang, Zhang Ying, Song Wei, Sun Yancui, Jiang Yinong
Department of Heart Intensive Care Unit, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
Front Cell Dev Biol. 2021 Aug 12;9:681790. doi: 10.3389/fcell.2021.681790. eCollection 2021.
The cleavage of osteopontin (OPN) by thrombin results in an N-terminal fragment (OPN-N), which exposes a cryptic integrin-binding motif that promotes the adherence of cells, and plays a proinflammatory role. However, the effect of OPN-N on abdominal aortic aneurysm (AAA) remains unknown. The aim of this study was to investigate the expression of OPN-N in aortic tissue samples obtained from patients, who underwent acute aortic dissection (AD), and normal aorta, effect of OPN-N on angiotensin (Ang) II-induced AAA in mice, and relationship between OPN-N and pyroptosis-related inflammatory factors . Hematoxylin and eosin staining was conducted to detect histological changes. Next, we detected the expression of the OPN-N protein. Additionally, ApoE-/- mice were divided into four groups: control, control + M5Ab (to block the OPN-N function in mice), Ang II, and Ang II + M5Ab. All mice were euthanized after a 28-day infusion and whole aortas, including thoracic and abdominal aortas, were collected for morphological and histological analysis of the AAA. The OPN-N protein expression was higher in patients with AD than in normal individuals, while histological changes in the aortas of Ang II mice were suppressed in Ang II + M5Ab mice. The expression of OPN-N, NOD-, LRR-, and pyrin domain-containing protein 3, pro-Caspase-1, ASC, Gasdermin-d, interleukin (IL)-18, IL-1β, matrix metalloproteinase (MMP) 2, and MMP9 was lower in the Ang II + M5Ab group than in the Ang II group. The gene expression of monocyte chemoattractant protein-1, IL-6, and tumor necrosis factor-α was suppressed in the aortic tissues of the Ang II + M5Ab group compared with the Ang II group. Moreover, the expression of α-smooth muscle actin was lower in the Ang II group than in the Ang II + M5Ab group. results showed that the increase in the expression of pyroptosis-related inflammatory factors induced by OPN was mediated through the nuclear factor (NF)-κB pathway. In conclusion, OPN-N promotes AAA by increasing the expression of pyroptosis-related inflammatory factors through the NF-κB pathway, inflammation, and extracellular matrix degradation. These results highlight the potential of OPN-N as a new therapeutic target to prevent AAA expansion.
凝血酶对骨桥蛋白（OPN）的切割产生一个N端片段（OPN-N），该片段暴露出一个隐藏的整合素结合基序，可促进细胞黏附，并发挥促炎作用。然而，OPN-N对腹主动脉瘤（AAA）的影响尚不清楚。本研究的目的是调查OPN-N在接受急性主动脉夹层（AD）患者的主动脉组织样本和正常主动脉中的表达、OPN-N对小鼠血管紧张素（Ang）II诱导的AAA的影响，以及OPN-N与焦亡相关炎症因子之间的关系。进行苏木精-伊红染色以检测组织学变化。接下来，我们检测了OPN-N蛋白的表达。此外，将载脂蛋白E基因敲除（ApoE-/-）小鼠分为四组：对照组、对照组 + M5抗体（以阻断小鼠体内OPN-N的功能）、Ang II组和Ang II + M5抗体组。所有小鼠在输注28天后实施安乐死，并收集包括胸主动脉和腹主动脉在内的整个主动脉，用于对AAA进行形态学和组织学分析。AD患者的OPN-N蛋白表达高于正常个体，而Ang II + M5抗体组小鼠抑制了Ang II组小鼠主动脉的组织学变化。Ang II + M5抗体组中OPN-N、含NOD样受体蛋白3、前半胱天冬酶-1、凋亡相关斑点样蛋白（ASC）、gasdermin-D、白细胞介素（IL）-18、IL-1β、基质金属蛋白酶（MMP）2和MMP9的表达低于Ang II组。与Ang II组相比，Ang II + M5抗体组主动脉组织中单核细胞趋化蛋白-1、IL-6和肿瘤坏死因子-α的基因表达受到抑制。此外，Ang II组中α-平滑肌肌动蛋白的表达低于Ang II + M5抗体组。结果表明，OPN诱导的焦亡相关炎症因子表达增加是通过核因子（NF）-κB途径介导的。总之，OPN-N通过NF-κB途径增加焦亡相关炎症因子的表达、炎症和细胞外基质降解来促进AAA。这些结果突出了OPN-N作为预防AAA扩展的新治疗靶点的潜力。
