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Lipocalin-2-induced proliferative endoplasmic reticulum stress participates in Kawasaki disease-related pulmonary arterial abnormalities

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Abstract

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.

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Acknowledgements

This work was supported by the following grants: the National Natural Science Foundation of China (91749108, 31671424, and 81322004 to H.M., 81200036 to M.L., and 81102006 to J.Z.), the Science and Technology Research and Development Program of Shaanxi Province, China (2018SF-101 to N.M. and 2019SF-008 to M.L.), and the Youth Innovation Team of Shaanxi Universities, China (to H.M., Y.Y., N.M., Y.W., and J.Z.).

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  1. Department of Pediatrics, Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, 712000, China

    Zhaoling Shi & Hui Ding

  2. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fourth Military Medical University, Xi’an, 710032, China

    Zhaoling Shi, Yue Yin, Chen Li, Nan Mu, Yishi Wang, Shanshan Jin, Heng Ma & Manling Liu

  3. Department of Endocrinology, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, China

    Jie Zhou

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  1. Zhaoling Shi
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Shi, Z., Yin, Y., Li, C. et al. Lipocalin-2-induced proliferative endoplasmic reticulum stress participates in Kawasaki disease-related pulmonary arterial abnormalities. Sci. China Life Sci. 64, 1000–1012 (2021). https://doi.org/10.1007/s11427-019-1772-8

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