Role and mechanism of copper overload-mediated endoplasmic reticulum stress in vascular endothelial injury in Kawasaki disease

Shi-Fang WEN; Zhi-Yuan TANG; Xian-Juan SHEN; Tao CHEN; Jian-Mei ZHAO

doi:10.7499/j.issn.1008-8830.2412085

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Chinese Journal of Contemporary Pediatrics ›› 2025, Vol. 27 ›› Issue (7) : 842-849. DOI: 10.7499/j.issn.1008-8830.2412085

EXPERIMENTAL RESEARCH

Role and mechanism of copper overload-mediated endoplasmic reticulum stress in vascular endothelial injury in Kawasaki disease

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Abstract

Objective To investigate the role and mechanism of copper overload-mediated endoplasmic reticulum stress (ERS) in vascular endothelial injury in Kawasaki disease (KD). Methods Four-week-old male C57BL/6 mice were randomly divided into four groups: control, KD, KD plus copper chelator tetrathiomolybdate (TTM), and KD plus ERS inhibitor AMG PERK 44 (AMG) (n=20 per group). A KD mouse model was established using Candida albicans extract. Human umbilical vein endothelial cells (HUVECs) were divided into control (intervention with healthy children's serum), KD (intervention with KD patients' serum), and KD+TTM (intervention with KD patients' serum plus 20 µmol/L TTM). Copper deposition in mouse heart tissue was assessed using rubeanic acid staining. Vascular pathological changes were observed using hematoxylin-eosin staining and measurement of abdominal aortic diameter and area. ERS activation was detected by transmission electron microscopy and immunofluorescence. HUVEC viability, apoptosis, and functional changes were evaluated using CCK8, flow cytometry, cell scratch assay, and angiogenesis experiments. ERS marker protein expression levels were measured by Western blot. Results Compared to the KD group, the KD+TTM and KD+AMG groups showed reduced copper deposition in the vascular wall, decreased swelling of coronary endothelial cells and endoplasmic reticulum, reduced inflammatory cell infiltration, and less abdominal aortic lesion expansion. The abdominal aortic diameter and area, and the fluorescence intensity of ERS marker proteins (GRP78 and CHOP) were significantly lower (P<0.05). Compared to the KD group, the KD+TTM group exhibited increased cell viability, tube number, and scratch healing rate, along with decreased apoptosis rate and expression of ERS marker proteins (GRP78, CHOP, ATF6, and p-PERK) (P<0.05). Conclusions Copper overload aggravates vascular endothelial injury in KD by activating the ERS pathway. TTM can exert protective effects on the endothelium by regulating copper metabolism and inhibiting the ERS pathway.

Key words

Kawasaki disease / Vascular endothelial injury / Endoplasmic reticulum stress / Copper chelator / Human umbilical vein endothelial cell / Mouse

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Shi-Fang WEN , Zhi-Yuan TANG , Xian-Juan SHEN , et al . Role and mechanism of copper overload-mediated endoplasmic reticulum stress in vascular endothelial injury in Kawasaki disease[J]. Chinese Journal of Contemporary Pediatrics. 2025, 27(7): 842-849 https://doi.org/10.7499/j.issn.1008-8830.2412085

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