Melatonin alleviates vascular endothelial cell damage by regulating an autophagy‐apoptosis axis in Kawasaki disease. Issue 6 (17th May 2022)

• Record Type: Journal Article
• Authors: Zheng, Yuanzheng; Huang, Saihua; Zhang, Jialing; Hou, Jia; Wu, Fang; Wang, Wenji; Han, Xiao; Gui, Yonghao
• Is Part Of: Cell proliferation. Volume 55:Issue 6(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-05-17
• Subjects: Cell proliferation -- Periodicals; 571.84
• DOI: 10.1111/cpr.13251
• Languages: English
• ISSNs: 0960-7722

Abstract

Abstract: Objectives: Melatonin has been reported to be an appropriate candidate for mitigating various cardiovascular injuries, owing to its versatility. This study aimed to explore the role of melatonin in Kawasaki disease (KD)‐associated vasculitis and its underlying mechanisms. Material and Methods: The role of melatonin was evaluated in human coronary artery endothelial cells (HCAECs), peripheral blood mononuclear cells from KD patients, human THP1 cell line in vitro, and a Candida albicans water‐soluble fraction (CAWS)‐induced KD mouse model in vivo. Cell proliferation assay, cell apoptosis assay, cell co‐culture, RNA extraction, RNA sequencing, reverse transcription quantitative PCR, enzyme‐linked immunosorbent assay (ELISA), transwell assay, western blot, dual‐luciferase reporter assay, and autophagic flux assay were performed to investigate the function and regulatory mechanisms of melatonin in vitro, while haematoxylin and eosin staining, Verhoeff's van Gieson staining, ELISA, and immunohistochemical analysis were performed to detect the effect of melatonin in vivo. Results: Melatonin suppressed cell apoptosis directly reduced the expression of endothelial cell damage markers in HCAECs, and alleviated vasculitis in the CAWS‐induced KD mouse model. Mechanistically, melatonin promoted autophagy by activating the melatonin/ melatonin receptor (MT)/cAMP‐response element binding protein (CREB) pathway and upregulating the expression of autophagy‐related gene‐3, thereby suppressing cell apoptosis in an autophagy‐dependent manner. Additionally, melatonin decreased the production of pro‐inflammatory cytokines in macrophages and indirectly reduced the immunopathological damage of HCAECs. Conclusions: This study revealed that melatonin protects vascular endothelial cells in KD, by suppressing cell apoptosis in an autophagy‐dependent manner and reducing the immunopathological damage mediated by macrophages. Abstract : KD‐related vasculitis is a crosstalk between vascular endothelial cells and immune cells, especially macrophages. Macrophages release pro‐inflammatory cytokines to mediate the damage of vascular endothelial cells, when the latter is injured, it can promote the former to secrete more pro‐inflammatory cytokines by releasing damage‐associated molecular pattern. Melatonin alleviates vascular endothelial cells injury directly by suppressing apoptosis in an autophagy‐dependent manner, it also decreases the production of pro‐inflammatory cytokines released by macrophages and reduces the immunopathological damage of vascular endothelial cells in KD‐related vasculitis.