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MicroRNA-125a-5p promotes NLRP3/caspase-1/GSDMD pathway-mediated pyroptosis in endothelial cells during Kawasaki
Ying Li1, Zhixiang Wu1, Min Kong1
1Department of Pediatrics, the Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
Abstract:
Kawasaki disease (KD) is an acute systemic vasculitis that the primary cause of secondary heart disease in children. Dysregulation of microRNA (miRNA) expression drives gene expression patterns across multiple biological processes, thereby mediating the pathogenesis and progression of KD. This study investigated how miR-125a-5p regulates pyroptosis in KD-associated endothelial cells. This study used Lactobacillus casei cell-wall extract (LCWE) to stimulate male C57BL/6 mice and human umbilical vein endothelial cells (HUVECs) to establish KD-like models. Experimental data demonstrated marked upregulation of miR-125a-5p expression in both KD-associated models. In vitro analysis revealed that targeted inhibition of miR-125a-5p increased HUVEC survival while reducing NLRP3/caspase-1/GSDMD-driven pyroptosis. In vivo, targeted inhibition of miR-125a-5p inactivated the NLRP3/caspase-1/GSDMD signaling pathway and diminished pyroptosis and inflammation in coronary artery tissues. This study found that miR-125a-5p exacerbates LCWE-induced pyroptosis in HUVECs and vascular injury in mice, suggesting a potential therapeutic strategy targeting miR-125a-5p for KD-related endothelial injury and inflammation.
Insights
MicroRNA-125a-5p worsens Kawasaki disease (KD) by promoting pyroptosis in endothelial cells. Inhibiting miR-125a-5p protects against KD-like vascular injury and inflammation.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Immunology
Background:
- Kawasaki disease (KD) is a leading cause of acquired heart disease in children, characterized by systemic vasculitis.
- MicroRNA (miRNA) dysregulation is implicated in KD pathogenesis, affecting gene expression and cellular processes.
- Endothelial cell dysfunction and pyroptosis are key features of KD vascular damage.
Purpose of the Study:
- To investigate the role of miR-125a-5p in regulating pyroptosis in Kawasaki disease.
- To elucidate the molecular mechanisms by which miR-125a-5p influences endothelial cell survival and inflammation in KD models.
- To assess the therapeutic potential of targeting miR-125a-5p in KD-associated endothelial injury.
Main Methods:
- Established Kawasaki disease-like models using Lactobacillus casei cell-wall extract (LCWE) in C57BL/6 mice and human umbilical vein endothelial cells (HUVECs).
- Quantified miR-125a-5p expression levels in KD models.
- Utilized in vitro and in vivo approaches to inhibit miR-125a-5p and assess its impact on pyroptosis (NLRP3/caspase-1/GSDMD pathway) and vascular inflammation.
Main Results:
- miR-125a-5p expression was significantly upregulated in both mouse and HUVEC KD models.
- Inhibition of miR-125a-5p enhanced HUVEC survival and reduced NLRP3/caspase-1/GSDMD-mediated pyroptosis.
- In vivo, miR-125a-5p inhibition suppressed the NLRP3/caspase-1/GSDMD pathway, decreasing pyroptosis and inflammation in coronary arteries.
Conclusions:
- miR-125a-5p exacerbates LCWE-induced pyroptosis in endothelial cells and contributes to vascular injury in a mouse model of KD.
- Targeting miR-125a-5p presents a potential therapeutic strategy for mitigating endothelial injury and inflammation in Kawasaki disease.
