Department of Cardiology, Children's Hospital of Soochow University, Suzhou, JiangSu province, China.
Department of Cardiology, Children's Hospital of Soochow University, Suzhou, JiangSu province, China; Department of Pediatrics, The First People's Hospital of Lianyungang, Xuzhou Medical University Affiliated Hospital of Lianyungang (Lianyungang Clinical College of Nanjing Medical University), Lianyungang, JiangSu province, China.
Int Immunopharmacol. 2024 Sep 30;139:112698. doi: 10.1016/j.intimp.2024.112698. Epub 2024 Jul 18.
Kawasaki disease (KD) is the most common cause of acquired heart disease in childhood. Coronary artery lesions (CALs) are serious complications of KD that can result in stenosis and thrombosis, but the specific underlying pathogenic mechanisms have not been elucidated. Therefore, exploring biomarkers to help predict early CALs is urgently needed for clinical treatment.
Patients were recruited from three independent cohorts. In the discovery cohort, Data-Independent Acquisition Mass Spectrometry (DIA-MS) was performed to screen plasma proteins from healthy controls (HCs), KD patients prior to intravenous immunoglobulin (IVIG) treatment, and KD patients post-IVIG treatment. KD patients were further divided into KD patients without CALs (nCAL) and with CALs (CALs) groups. Bioinformatic analysis was carried out for the differentially expressed proteins (DEPs) and hub proteins. Candidate proteins were quantified by enzyme-linked immunosorbent assay (ELISA) in the validation cohort 1 and 2. Furthermore, candida albicans cell wall extract (CAWS)-induced KD vasculitis mice and cell models were established to investigate the expression of biomarkers identified in the aforementioned clinical cohort.
According to the quantitative proteomics analysis, SERPINE1 was significantly increased in KD patients with CALs. Receiver operating characteristic curves (ROC) revealed that plasma SERPINE1 exhibited greater ability in predicting CALs (AUC = 0.824, P < 0.0001). After IVIG treatment, the concentrations of SERPINE1 in the nCALs group significantly decreased. However, the concentration of SERPINE1 remained persistently elevated in the CALs group. Moreover, the expression of SERPINE1 was significantly upregulated in the heart tissue of KD mice, KD plasma, or tumor necrosis factor-α (TNF-α)-stimulated human coronary artery endothelial cells (HCAECs).
Overall, our results suggest that the plasma concentration of SERPINE1 might serve as a new potential predictive biomarker for CALs in KD patients.
川崎病（KD）是儿童获得性心脏病的最常见原因。冠状动脉病变（CALs）是 KD 的严重并发症，可导致狭窄和血栓形成，但具体的潜在发病机制尚未阐明。因此，迫切需要探索生物标志物来帮助预测早期 CALs，以进行临床治疗。
患者来自三个独立的队列。在发现队列中，采用数据非依赖性采集质谱法（DIA-MS）筛选健康对照者（HCs）、静脉注射免疫球蛋白（IVIG）治疗前的 KD 患者和 IVIG 治疗后的 KD 患者的血浆蛋白。KD 患者进一步分为无 CALs（nCAL）和有 CALs（CALs）组。对差异表达蛋白（DEPs）和枢纽蛋白进行生物信息学分析。候选蛋白在验证队列 1 和 2 中通过酶联免疫吸附测定（ELISA）进行定量。此外，建立白念珠菌细胞壁提取物（CAWS）诱导的 KD 血管炎小鼠和细胞模型，以研究上述临床队列中鉴定的生物标志物的表达。
根据定量蛋白质组学分析，SERPINE1 在有 CALs 的 KD 患者中明显增加。接受者操作特征曲线（ROC）显示，血浆 SERPINE1 预测 CALs 的能力更强（AUC=0.824，P<0.0001）。IVIG 治疗后，nCALs 组中 SERPINE1 的浓度显著降低。然而，CALs 组中 SERPINE1 的浓度仍然持续升高。此外，KD 小鼠心脏组织、KD 血浆或肿瘤坏死因子-α（TNF-α）刺激的人冠状动脉内皮细胞（HCAECs）中 SERPINE1 的表达明显上调。
总的来说，我们的结果表明，SERPINE1 的血浆浓度可能成为 KD 患者 CALs 的新潜在预测生物标志物。
