Lipocalin-2-induced proliferative endoplasmic reticulum stress participates in Kawasaki disease-related pulmonary arterial abnormalities
Lipocalin-2-induced proliferative endoplasmic reticulum stress participates in Kawasaki disease-related pulmonary arterial abnormalities
复制标题
Lipocalin-2诱导的增殖性内质网应激参与川崎病相关的肺动脉异常
DOI：
10.1007/s11427-019-1772-8
复制
发表时间：
--
期刊：
影响因子：
--
通讯作者：
Zhou J
中科院分区：
文献类型：
--
作者：
Shi ZL;Yin Y;Li C;Ding H;Mu N;Wang YS;Jin SS;Ma H;Liu ML;Zhou J
临床病例报道川崎病（KD）患者出现肺动脉结构和功能异常；然而，其根本机制尚不清楚。本研究通过腹腔注射干酪乳杆菌细胞壁提取物（LCWE）建立KD大鼠模型。结果表明，KD 大鼠的肺动脉功能和结构异常。此外，在 KD 大鼠的肺动脉中观察到增殖性内质网应激（ER 应激）。值得注意的是，KD 大鼠血浆和肺组织中炎症触发因子 lipocalin-2 (Lcn 2) 的水平显着升高。 LCWE 刺激后 Lcn 2 水平升高可能是由多形核中性粒细胞 (PMN) 引起的。相应地，在培养的肺动脉平滑肌细胞（PASMC）中，Lcn 2显着增强激活转录因子6（ATF6）的裂解和核定位，上调葡萄糖调节蛋白78（GRP78）和神经突生长抑制剂（NOGO）的转录，并促进PASMC增殖。然而，促凋亡 C/EBP 同源蛋白 (CHOP) 和 caspase 12 水平并未升高。 4-苯基丁酸（4-PBA，一种 ER 应激的特异性抑制剂）治疗可抑制 Lcn 2 诱导的 PASMC 增殖，减轻 KD 大鼠的肺动脉异常和右心室肥厚，并降低右心室收缩压。总之，Lcn 2 显着促进 PASMC 中的增殖 ER 应激，这可能是 KD 相关肺动脉异常的原因。
Clinical cases have reported pulmonary arterial structural and functional abnormalities in patients with Kawasaki disease (KD); however, the underlying mechanisms are unclear. In this study, a KD rat model was established via the intraperitoneal injection ofLactobacillus caseicell wall extract (LCWE). The results showed that pulmonary arterial functional and structural abnormalities were observed in KD rats. Furthermore, proliferative endoplasmic reticulum stress (ER stress) was observed in the pulmonary arteries of KD rats. Notably, the level of lipocalin-2 (Lcn 2), a trigger factor of inflammation, was remarkably elevated in the plasma and lung tissues of KD rats; increased Lcn 2 levels following LCWE stimulation may result from polymorphonuclear neutrophils (PMNs). Correspondingly, in cultured pulmonary artery smooth muscle cells (PASMCs), Lcn 2 markedly augmented the cleavage and nuclear localization of activating transcription factor-6 (ATF6), upregulated the transcription of glucose regulated protein 78 (GRP78) and neurite outgrowth inhibitor (NOGO), and promoted PASMCs proliferation. However, proapoptotic C/EBP homologous protein (CHOP) and caspase 12 levels were not elevated. Treatment with 4-phenyl butyric acid (4-PBA, a specific inhibitor of ER stress) inhibited PASMCs proliferation induced by Lcn 2 and attenuated pulmonary arterial abnormalities and right ventricular hypertrophy and reduced right ventricular systolic pressure in KD rats. In conclusion, Lcn 2 remarkably facilitates proliferative ER stress in PASMCs, which probably accounts for KD-related pulmonary arterial abnormalities.