Department of Cardiovascular Surgery, Binzhou Medical University Hospital, Binzhou, 256600, Shandong Province, China.
Department of Medical Research Center, Binzhou Medical University Hospital, Binzhou, 256600, Shandong Province, China.
Sci Rep. 2024 Apr 30;14(1):9960. doi: 10.1038/s41598-024-60737-9.
The pathogenesis of aortic dissection (AD), an aortic disease associated with high mortality, involves significant vascular inflammatory infiltration. However, the precise relationship between perivascular adipose tissue (PVAT) and aortic dissection remains incompletely understood. The objective of this study is to investigate the role of PVAT inflammation in the pathogenesis of aortic dissection and identify novel therapeutic targets for this disease. The mouse model of aortic dissection was established in this study through intraperitoneal injection of Ang II and administration of BAPN in drinking water. Additionally, control groups were established at different time points including the 2-week group, 3-week group, and 4-week group. qPCR and immunohistochemistry techniques were employed to detect the expression of inflammatory markers and RUNX1 in PVAT surrounding the thoracic aorta in mice. Additionally, an aortic dissection model was established using RUNX1 knockout mice, and the aforementioned indicators were assessed. The 3T3-L1 cells were induced to differentiate into mature adipocytes in vitro, followed by lentivirus transfection for the knockdown or overexpression of RUNX1. The study aimed to investigate the potential cell-to-cell interactions by co-culturing 3T3-L1 cells with A7r5 or RAW264.7 cells. Subsequently, human aortic PVAT samples were obtained through clinical surgery and the aforementioned indicators were detected. In comparison to the control group, the aortic dissection model group exhibited decreased expression of MMP-2 and NF-κB in PVAT, while TNF-α and RUNX1 expression increased. Suppression of RUNX1 expression resulted in increased MMP-2 and NF-κB expression in PVAT, along with decreased TNF-α expression. Overexpression of RUNX1 upregulated the expression levels of NF-Κb, MMP-2, and TNF-α in adipocytes, whereas knockdown of RUNX1 exerted an opposite effect. Macrophages co-cultured with adipocytes overexpressing RUNX1 exhibited enhanced CD86 expression, while vascular smooth muscle cells co-cultured with these adipocytes showed reduced α-SMA expression. In human samples, there was an increase in both RUNX1 and MMP-2 expression levels, accompanied by a decrease in TNF-α and NF-Κb expression. The presence of aortic dissection is accompanied by evident inflammatory alterations in the PVAT, and this phenomenon appears to be associated with the involvement of RUNX1. It is plausible that the regulation of PVAT's inflammatory changes by RUNX1/NF-κB signaling pathway plays a role in the pathogenesis of aortic dissection.
主动脉夹层（AD）是一种与高死亡率相关的主动脉疾病，其发病机制涉及到显著的血管炎症浸润。然而，关于血管周围脂肪组织（PVAT）与主动脉夹层之间的确切关系仍不完全清楚。本研究旨在探讨 PVAT 炎症在主动脉夹层发病机制中的作用，并为该疾病确定新的治疗靶点。本研究通过腹腔注射 Ang II 和在饮用水中给予 BAPN 建立了小鼠主动脉夹层模型，并设立了不同时间点的对照组，包括 2 周组、3 周组和 4 周组。采用 qPCR 和免疫组织化学技术检测小鼠胸主动脉周围 PVAT 中炎症标志物和 RUNX1 的表达。此外，还使用 RUNX1 基因敲除小鼠建立了主动脉夹层模型，并评估了上述指标。将 3T3-L1 细胞在体外诱导分化为成熟脂肪细胞，然后通过慢病毒转染敲低或过表达 RUNX1。本研究旨在通过共培养 3T3-L1 细胞与 A7r5 或 RAW264.7 细胞来研究潜在的细胞间相互作用。随后，通过临床手术获得人主动脉 PVAT 样本，并检测上述指标。与对照组相比，主动脉夹层模型组 PVAT 中 MMP-2 和 NF-κB 的表达降低，而 TNF-α和 RUNX1 的表达增加。抑制 RUNX1 的表达导致 PVAT 中 MMP-2 和 NF-κB 的表达增加，同时 TNF-α的表达降低。RUNX1 的过表达上调了脂肪细胞中 NF-Κb、MMP-2 和 TNF-α的表达水平，而 RUNX1 的敲低则产生相反的效果。与过表达 RUNX1 的脂肪细胞共培养的巨噬细胞 CD86 表达增强，而与这些脂肪细胞共培养的血管平滑肌细胞 α-SMA 表达减少。在人样本中，RUNX1 和 MMP-2 的表达水平增加，同时 TNF-α和 NF-Κb 的表达水平降低。主动脉夹层的存在伴随着 PVAT 中明显的炎症改变，这种现象似乎与 RUNX1 的参与有关。因此，RUNX1/NF-κB 信号通路对 PVAT 炎症变化的调节可能在主动脉夹层的发病机制中起作用。
