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. 2021 Jun;64(6):1000-1012.
doi: 10.1007/s11427-019-1772-8. Epub 2020 Sep 9.

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

Zhaoling Shi #  1   2 , Yue Yin #  2 , Chen Li  2 , Hui Ding  1 , Nan Mu  2 , Yishi Wang  2 , Shanshan Jin  2 , Heng Ma  3 , Manling Liu  4 , Jie Zhou  5
Affiliations

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

Zhaoling Shi et al. Sci China Life Sci. 2021 Jun.

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.

Keywords: Kawasaki disease; endoplasmic reticulum stress; lipocalin-2; pulmonary arterial structural and functional abnormalities.

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