Lipocalin-2-induced proliferative endoplasmic reticulum stress participates in Kawasaki disease-related pulmonary arteri
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pocalin-2-induced proliferative endoplasmic reticulum stress participates in Kawasaki disease-related pulmonary arterial abnormalities 1,2†
Zhaoling Shi
2†
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, Yue Yin , Chen Li , Hui Ding , Nan Mu , Yishi Wang , Shanshan Jin , 2* 2* 3* Heng Ma , Manling Liu & Jie Zhou
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Department of Pediatrics, Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang 712000, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fourth Military Medical University, Xi’an 710032, China; 3 Department of Endocrinology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China Received July 8, 2019; accepted June 30, 2020; published online September 9, 2020
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 of Lactobacillus casei cell 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. Kawasaki disease, lipocalin-2, endoplasmic reticulum stress, pulmonary arterial structural and functional abnormalities Citation:
Shi, Z., Yin, Y., Li, C., Ding, H., Mu, N., Wang, Y., Jin, S., Ma, H., Liu, M., and Zhou, J. (2020). Lipocalin-2-induced proliferative endoplasmic reticulum stress participates in Kawasaki disease-related pulmonary arterial abnormalities. Sci China Life Sci 63, https://doi.org/10.1007/s11427-0191772-8
INTRODUCTION Kawasaki disease (KD) is an acute systemic vasculitis predominantly afflicting children (McCrindle et al., 2017). Although it is somehow self-limiting, 25% of untreated patients
†Contributed equally to this work *Corresponding authors (Jie Zhou, email: zhouji
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