Wan Yang , Wenli Guo , Zhouping Wang , Linjie Jiang , Xilian Luo , Kaining Chen , Xiaofang Liu , Can An , Lei Pi , Yufen Xu , Lanyan Fu , Huazhong Zhou , Xiaoqiong Gu , Di Che , Jianrui Wei , Hongyan Yu
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引用次数: 0
Abstract
Purpose
Kawasaki disease (KD) is an acute systemic vasculitis and a leading cause of acquired heart disease in children in developed countries. This study endeavors to explore the role and underlying mechanisms of EIF2AK3 in KD-related vasculitis, thereby offering novel therapeutic perspectives.
Methods
DNA from 910 KD patients and 848 controls were genotyped for rs13045 using TaqMan® to analyze the association with KD susceptibility. Concurrently, EIF2AK3 expression under KD inflammatory conditions was assessed using qRT-PCR, Western blot, and immunofluorescence. Pro-inflammatory cytokine levels were measured following EIF2AK3 knockdown or overexpression, and RNA sequencing was explored the downstream signaling pathways. For in vivo experiment, a Lactobacillus casei cell wall extract (LCWE)-induced KD mouse model with Eif2ak3 knockdown was established. ELISA and HE staining were used to investigate the degree of vasculitis between Eif2ak3 knockdown and control groups.
Results
The EIF2AK3/rs13045 polymorphism was associated with KD susceptibility, with the rs13045 C allele downregulating EIF2AK3. EIF2AK3 expression was increased significantly during KD inflammatory conditions. EIF2AK3 knockdown or pharmacological inhibition (GSK2606414) reduced pro-inflammatory cytokines (IL-1β/IL-6/IL-8/TNF-α) expression, while overexpression of EIF2AK3 elevated them. Mechanistically, EIF2AK3 promoted pro-inflammatory cytokines expression through activation of the MAPK-ERK1/2 pathway. Furthermore, EIF2AK3 downregulation inhibited the endothelial-to-mesenchymal transition (EndoMT), thereby impairing HUVECs migration. These findings were also recapitulated in the KD mouse model.
Conclusion
EIF2AK3/rs13045 is a novel susceptibility locus for KD in the southern Chinese population. Our findings reveal that EIF2AK3 upregulates pro-inflammatory cytokines, thereby promoting KD-associated vasculitis via the MAPK-ERK1/2 pathway. This discovery suggests EIF2AK3 as a potential therapeutic target for the management of KD.
期刊介绍:
BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.