Department of Paediatrics, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.
Medical College of Nantong university, Nantong, 226001, Jiangsu, People's Republic of China.
Eur J Med Res. 2020 Mar 17;25(1):8. doi: 10.1186/s40001-020-00406-5.
Kawasaki disease (KD) is a common, yet unknown etiology disease in Asian countries, which causes acquired heart disease in childhood. It is characterized by an inflammatory acute febrile vasculitis of medium-sized arteries, particularly the coronary arteries. High-mobility group box-1 protein (HMGB1) is a non-histone chromosomal-binding protein present in the nucleus of eukaryotic cells, which contains 215 amino acid residues. Although the cellular signal transduction mechanisms of HMGB1 are currently unclear, the important role of the receptor for advanced glycation end-products (RAGE), the main receptor for HMGB1 has been reported in detail. The purpose of our study was to verify the mechanism and clinical significance of HMGB1-RAGE in coronary artery injury of Kawasaki disease.
52 blood samples of patients in KD were collected, and the coronary artery Z score was calculated according to the echocardiographic results. The Z score ≥ 2.0 was classified as coronary artery lesions (CAL); otherwise, it was no-coronary artery lesions (NCAL). In addition, the fever group and control group were set. Among them, the fever group were children with fever due to respiratory tract infection at the same time period as KD (heat peak ≥ 38.5 ℃). The normal group were children at a routine physical examination in the outpatient clinic of Nantong University and the physical examination center of the child care insurance, and there were no infectious diseases and heart diseases. The serum levels of HMGB1, RAGE, and NF-κB in each group were detected by ELISA. The animal model of KD was established using the New Zealand young rabbits. We used RT-qPCR/H&E staining/immunohistochemistry/ELISA and western blot to detect the level of HMGB1/RAGE and NF-κB.
In this study, we found that the HMGB1/RAGE/NF-κB axis was elevated in the serum of children with KD. In addition, an animal model of KD was subsequently prepared to examine the pathological changes of the coronary arteries. We found that the serum levels of HMGB1/RAGE/NF-κB in rabbits with KD were significantly higher than those of the control group. Moreover, the lumen diameter of the coronary artery was slightly enlarged, and the wall of the tube became thinner and deformed. In addition, the HMGB1/RAGE/NF-κB levels in the coronary artery were higher in the rabbits with KD in the acute phase.
On the whole, the findings of this study demonstrate that the expression of HMGB1/RAGE/NF-κB is altered at different stages of KD, suggesting that the HMGB1/RAGE/NF-κB signaling pathway plays an important role in vascular injury in KD. The results of this study may have important implications for the early warning of coronary artery lesions in KD.
川崎病（KD）是亚洲国家常见但病因不明的疾病，可导致儿童后天性心脏病。它的特征是中等大小动脉的炎症性急性发热性脉管炎，特别是冠状动脉。高迁移率族蛋白 B1（HMGB1）是真核细胞核内的非组蛋白染色体结合蛋白，包含 215 个氨基酸残基。虽然 HMGB1 的细胞信号转导机制尚不清楚，但作为其主要受体的晚期糖基化终产物受体（RAGE）的重要作用已被详细报道。我们研究的目的是验证 HMGB1-RAGE 在川崎病冠状动脉损伤中的机制和临床意义。
收集 52 例川崎病患者的血液样本，根据超声心动图结果计算冠状动脉 Z 评分。Z 评分≥2.0 为冠状动脉病变（CAL）；否则为无冠状动脉病变（NCAL）。此外，还设置了发热组和对照组。其中，发热组为同时期因呼吸道感染而发热的川崎病患儿（热峰≥38.5℃）。正常组为南通大学门诊和儿童保健保险体检中心常规体检的儿童，无传染病和心脏病。通过 ELISA 检测各组血清 HMGB1、RAGE 和 NF-κB 水平。采用新西兰幼兔建立川崎病动物模型。采用 RT-qPCR/H&E 染色/免疫组化/ELISA 和 Western blot 检测 HMGB1/RAGE 和 NF-κB 水平。
本研究发现，川崎病患儿血清中 HMGB1/RAGE/NF-κB 轴升高。此外，随后制备了川崎病动物模型，以检查冠状动脉的病理变化。我们发现，KD 兔血清中 HMGB1/RAGE/NF-κB 水平明显高于对照组。此外，冠状动脉的管腔直径稍增大，管壁变薄变形。此外，KD 兔急性期冠状动脉 HMGB1/RAGE/NF-κB 水平较高。
总的来说，本研究结果表明，HMGB1/RAGE/NF-κB 在川崎病的不同阶段表达发生改变，提示 HMGB1/RAGE/NF-κB 信号通路在川崎病血管损伤中发挥重要作用。本研究结果可能对川崎病冠状动脉病变的早期预警具有重要意义。
